CA2440108A1

CA2440108A1 - Therapeutic polypeptides, nucleic acids encoding same, and methods of use

Info

Publication number: CA2440108A1
Application number: CA002440108A
Authority: CA
Inventors: Ramesh Kekuda; Velizar T. Tchernev; Xiaohong Liu; Kimberly A. Spytek; Meera Patturajan; Catherine E. Burgess; Corine A. M. Vernet; Li Li; Linda Gorman; Uriel M. Malyankar; Ferenc L. Boldog; Xiaojia Guo; Suresh G. Shenoy; Muralidhara Padigaru; Raymond J. Taupier, Jr.; Charles E. Miller; Stacie J. Casman; Carol E. A. Pena; Esha A. Gangolli; Vladimir Gusev
Original assignee: Individual
Current assignee: CuraGen Corp
Priority date: 2001-03-08
Filing date: 2002-03-08
Publication date: 2002-10-10
Also published as: JP2005505247A

Abstract

Diclosed herein are nucleic acid sequences that encode G-coupled protein- receptor related polypeptides. Also disclosed are polypeptides encoded by these nucleic acid sequences, and antibodies, which immunospecifically-bind to the polypeptide, as well as derivatives, variants mutants, or fragments of t he aforementioned polypeptide, polynucleotide, or antibody. The invention furth er disclodes therapeutic, diagnostic and research methods for diagnosis, treatment, and prevention of disorders involving any one of these novel huma n nucleic acids and proteins.

Description

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PLUS D'UN TOME.

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THERAPEUTIC POLYPEPTIDES, NUCLEIC ACIDS ENCODING
SAME, AND METHODS OF USE
FIELD OF THE INVENTION
The present invention relates to novel polypeptides having properties related to stimulation of biochemical or physiological responses in a cell, a tissue, an organ or an organism. More particularly, the novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use encompass diagnostic and prognostic assay procedures as well as methods of treating diverse pathological conditions.
BACKGROUND OF THE INVENTION
Eukaryotic cells are characterized by biochemical and physiological processes, which under normal conditions are exquisitely balanced to achieve the preservation and propagation of the cells. When such cells are components of multicellular organisms such as vertebrates or, more particularly, organisms such as mammals, the regulation of the biochemical and physiological processes involves intricate signaling pathways. Frequently, such signaling pathways include constituted of extracellular signaling proteins, cellular receptors that bind the signaling proteins and signal transducing components located within the cells.
Signaling proteins may be classified as endocrine effectors, paracrine effectors or autocrine effectors. Endocrine effectors are signaling molecules secreted by a given organ into the circulatory system, which are then transported to a distant target organ or tissue. The target cells include the receptors for the endocrine effector, and when the endocrine effector binds, a signaling cascade is induced. Paracrine effectors involve secreting cells and receptor cells in close proximity to each other, such as two different classes of cells in the same tissue or organ. One class of cells secretes the paracrine effector, which then reaches the second class of cells, for example by diffusion through the extracellular fluid. The second class of cells contains the receptors for the paracrine effector; binding of the effector results in induction of the signaling cascade that elicits the corresponding biochemical or physiological effect. Autocrine effectors are highly analogous to paracrine effectors, except that the same cell type that secretes the autocrine effector also contains the receptor.
Thus the autocrine effector binds to receptors on the same cell, or on identical neighboring cells. The binding process then elicits the characteristic biochemical or physiological effect.
Signaling processes may elicit a variety of effects on cells and tissues including by way of nonlimiting example, induction of cell or tissue proliferation, suppression of growth or proliferation, induction of differentiation or maturation of a cell or tissue, and suppression of differentiation or maturation of a cell or tissue.
Many pathological conditions involve dysregulation of expression of important effector proteins. In certain classes of pathologies the dysregulation is manifested as diminished or suppressed level of synthesis and secretion of protein effectors. In a clinical setting a subject may be suspected of suffering from a condition brought on by diminished or suppressed levels of a protein effector of interest. Therefore there is a need to assay for the level of the protein effector of interest in a biological sample from such a subject, and to compare the level with that characteristic of a nonpathological condition.
There also is a need to provide the protein effector as a product of manufacture. Administration of the effector to a subject in need thereof is useful in treatment of the pathological condition.
Accordingly, there is a need for a method of treatment of a pathological condition brought on by a diminished or suppressed levels of the protein effector of interest.
SUMMARY OF THE INVENTION
The invention is based in part upon the discovery of isolated polypeptides including amino acid sequences selected from mature forms of the amino acid sequences selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86. The invention also is based in part upon variants of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 1 S% of the amino acid residues in the sequence of the mature form are so changed. In another embodiment, the invention includes the amino acid sequences selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86. In another embodiment, the invention also comprises variants of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed. The invention also involves fragments of any of the mature forms of the amino acid sequences selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, or any other amino acid sequence selected from this group.
The invention also comprises fragments from these groups in which up to 15% of the residues are changed.
In another embodiment, the invention encompasses polypeptides that are naturally occurnng allelic variants of the sequence selected from the group consisting of SEQ ID NO:
S 2n, wherein n is an integer between 1 and 86. These allelic variants include amino acid sequences that are the translations of nucleic acid sequences differing by a single nucleotide from nucleic acid sequences selected from the group consisting of SEQ ID NOS:
2n-1, wherein n is an integer between 1 and 86. The variant polypeptide where any amino acid changed in the chosen sequence is changed to provide a conservative substitution.
In another embodiment, the invention comprises a pharmaceutical composition involving a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86 and a pharmaceutically acceptable Garner. In another embodiment, the invention involves a kit, including, in one or more containers, this pharmaceutical composition.
In another embodiment, the invention includes the use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease being selected from a pathology associated with a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86 wherein said therapeutic is the polypeptide selected from this group.
In another embodiment, the invention comprises a method for determining the presence or amount of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86 in a sample, the method involving providing the sample; introducing the sample to an antibody that binds immunospecifically to the polypeptide; and determining the presence or amount of antibody bound to the polypeptide, thereby determining the presence or amount of polypeptide in the sample.
In another embodiment, the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86 in a first mammalian subject, the method involving measuring the level of expression of the polypeptide in a sample from the first mammalian subject;
and comparing the amount of the polypeptide in this sample to the amount of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, the disease, wherein an alteration in the expression level of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.
In another embodiment, the invention involves a method of identifying an agent that binds to a polypeptide with an amino acid sequence selected from the group consisting of SEQ
ID NO: 2n, wherein n is an integer between 1 and 86, the method including introducing the polypeptide to the agent; and determining whether the agent binds to the polypeptide. The agent could be a cellular receptor or a downstream effector.
In another embodiment, the invention involves a method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, the method including providing a cell expressing the polypeptide of the invention and having a property or function ascribable to the polypeptide;
contacting the cell with a composition comprising a candidate substance; and determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition devoid of the substance, the substance is identified as a potential therapeutic agent.
In another embodiment, the invention involves a method for screening for a modulator of activity or of latency or predisposition to a pathology associated with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, the method including administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of the invention, wherein the test animal recombinantly expresses the polypeptide of the invention;
measuring the activity of the polypeptide in the test animal after administering the test compound; and comparing the activity of the protein in the test animal with the activity of the polypeptide in a control animal not administered the polypeptide, wherein a change in the activity of the polypeptide in the .
test animal relative to the control animal indicates the test compound is a modulator of latency of, or predisposition to, a pathology associated with the polypeptide of the invention. The recombinant test animal could express a test protein transgene or express the transgene under the control of a promoter at an increased level relative to a wild-type test animal The promoter may or may not b the native gene promoter of the transgene.
In another embodiment, the invention involves a method for modulating the activity of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:
2n, wherein n is an integer between 1 and 86, the method including introducing a cell sample expressing the polypeptide with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide.
In another embodiment, the invention involves a method of treating or preventing a pathology associated with a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, the method including administering the polypeptide to a subject in which such treatment or prevention is desired in an amount sufficient to treat or prevent the pathology in the subject. T'he subject could be human.
In another embodiment, the invention involves a method of treating a pathological state in a mammal, the method including administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86 or a biologically active fragment thereof.
In another embodiment, the invention involves an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide having an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID
NO: 2n, wherein n is an integer between 1 and 86; a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 1 S% of the amino acid residues in the sequence of the mature form are so changed; the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86; a variant of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ
ID NO: 2n, wherein n is an integer between 1 and 86 or any variant of the polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and the complement of any of the nucleic acid molecules.
In another embodiment, the invention comprises an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID
NO: 2n, wherein n is an integer between 1 and 86, wherein the nucleic acid molecule comprises the nucleotide sequence of a naturally occurnng allelic nucleic acid variant.
In another embodiment, the invention involves an isolated nucleic acid molecule including a nucleic acid sequence encoding a polypeptide having an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID
NO: 2n, wherein n is an integer between 1 and 86 that encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant.
In another embodiment, the invention comprises an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID
NO: 2n, wherein n is an integer between 1 and 86, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ
ID NOS: 2n-1, wherein n is an integer between 1 and 86.
In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID
NO: 2n, wherein n is an integer between 1 and 86, wherein the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 86; a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 86 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; a nucleic acid fragment of the sequence selected from the group consisting of SEQ
ID NO: 2n-1, wherein n is an integer between 1 and 86; and a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ
ID NO: 2n-1, wherein n is an integer between 1 and 86 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed.
In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID

NO: 2n, wherein n is an integer between 1 and 86, wherein the nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 86, or a complement of the nucleotide sequence.
In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID
NO: 2n, wherein n is an integer between 1 and 86, wherein the nucleic acid molecule has a nucleotide sequence in which any nucleotide specified in the coding sequence of the chosen nucleotide sequence is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 1 S% of the nucleotides in the chosen coding sequence are so changed, an isolated second polynucleotide that is a complement of the first polynucleotide, or a fragment of any of them.
In another embodiment, the invention includes a vector involving the nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 86. This vector can have a promoter operably linked to the nucleic acid molecule. This vector can be located within a cell.
In another embodiment, the invention involves a method for determining the presence or amount of a nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 86 in a sample, the method including providing the sample; introducing the sample to a probe that binds to the nucleic acid molecule; and determining the presence or amount of the probe bound to the nucleic acid molecule, thereby determining the presence or amount of the nucleic acid molecule in the sample. The presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type. The cell type can be cancerous.
In another embodiment, the invention involves a method for determining the presence of or predisposition for a disease associated with altered levels of a nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID
NO: 2n, wherein n is an integer between 1 and 86 in a first mammalian subject, the method including measuring the amount of the nucleic acid in a sample from the first mammalian subject; and comparing the amount of the nucleic acid in the sample of step (a) to the amount of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description and claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel nucleotides and polypeptides encoded thereby.
Included in the invention are the novel nucleic acid sequences, their encoded polypeptides, antibodies, and other related compounds. The sequences are collectively referred to herein as "NOVX nucleic acids" or "NOVX polynucleotides" and the corresponding encoded polypeptides are referred to as "NOVX polypeptides" or "NOVX proteins." Unless indicated otherwise, "NOVX" is meant to refer to any of the novel sequences disclosed herein. Table 1 provides a summary of the NOVX nucleic acids and their encoded polypeptides.
TABLE 1. Sequences and Corresponding SEQ ID Numbers SEQ
NOVX Internal IdentificationID SEQ ID Homology Assignment NO NO
(nucleic(polypeptide) acid la CG58548-O1 1 2 Neurexo hilin 1 Precursor-like 1b 174307940 3 4 Neurexo hilin 1 Precursor-like lc CG58548-02 5 6 Neurexo hilin 1 Precursor-like 1d CG58548-03 7 8 Neurexo hilin 1 Precursor-like 2a CG58542-O1 9 10 Neuro hilin-like 2b 169679583 11 12 Neurophilin-like 2c 169679634 13 14 Neurophilin-like 3a CG58540-Oi 15 16 Cytoplasmic-Antiproteinase 3-like 4a CG56340-03 17 18 Interferon-like 4b 174308150 19 20 Interferon-like Sa CG58514-O1 21 22 Le recan-like 6a CG57887-O1 23 24 Tumor suppressor-like 7a CG57885-O1 25 26 Procholoecytstokinin Precursor-like 8a CG57865-O1 27 28 Secreted rotein-like 8b 171651532 29 30 Secreted rotein-like 9a CG54503-03 31 32 Gliacolin -like 10a CG58600-O1 33 34 Olfactomedin-like lla CG57572-O1 35 36 CMP-N-Acetylneuraminate-beta-galactosamide-alpha-2,3-sial ltransferase like 12a CG57518-O1 37 38 Neural cell adhesion protein Big-2 recursor-like 12b 170108372 39 40 Neural cell adhesion protein Big-2 recursor-like 12c 170108393 41 42 Neural cell adhesion protein Big-2 recursor-like 12d 170343246 43 44 Neural cell adhesion protein Big-2 precursor-like 12e 170343692 45 46 Neural cell adhesion protein Big-2 recursor-like 12f 170684238 47 48 Neural cell adhesion protein Big-2 precursor-like 12g 170534177 49 50 Neural cell adhesion protein Big-2 recursor-like 13a CG57409-03 51 52 Neural cell adhesion protein Big-2 recursor-like 13b CG57409-OS 53 54 MAM and Ig domain-containing rotein-like 13c CG57409-06 SS 56 MAM and Ig domain-containing rotein 14a CG59262-O1 57 58 Calcium bindling protein like 15a CG58635-O1 59 60 S-100-like 15b CG58635-02 61 62 Secretory carrier membrane protein-like 15c CG58635-03 63 64 Secretory carrier membrane protein-like 16a CG59209-O1 65 66 CG3714-like 16b 174308417 67 68 CG3714-like 16c 174308429 69 70 CG3714-like 17a CG59368-O1 71 72 Preoptic regulatory factor-2-like 18a CG58628-O1 73 74 Adi o hilin-like 18b 174228350 75 76 Adi o hilin-like 18c 174228354 77 78 Adi o hilin-like 18d 188888733 79 80 Adi o hilin-like 19a CG59342-O1 81 82 FIS-like 20a CG59486-Ol 83 84 Zn finger protein-like 21 a CG59446-O1 85 86 Neurotransmission associated rotein-like 21b 174308261 87 88 Neurotransmission associated protein-like 21c 174308266 89 90 Neurotransmission associated rotein-like 21d 174308278 91 92 Neurotransmission associated rotein-like 21e 174308283 93 94 Neurotransmission associated protein-like a 21f 174308287 95 96 Neurotransmission associated rotein-like 21g 174308293 97 98 Neurotransmission associated rotein-like 21h 174308301 99 100 Neurotransmission associated protein-like 21i 174308311 101 102 Neurotransmission associated rotein-like 21 j 174308315 103 104 Neurotransmission associated protein-like 21k 174308321 105 106 Neurotransmission associated rotein-like 211 174308327 107 108 Neurotransmission associated rotein-like 21m 174308337 109 110 Neurotransmission associated rotein-like 21n CG59446-02 111 112 Neurotransmission associated rotein-like 22a CG59375-O1 113 114 Drebrin -like 23a CG59321-O1 115 116 UNCSH2-like 23b CG59321-02 117 118 UNCSH2-like 24a CG59591-O1 119 120 Trypsin inhibitor-like 25a CG59588-01 121 122 ISLR ecursor-like 26a CG59584-O1 123 124 Ovostatin recursor-like 266 CG59584-02 125 126 Ovostatin recursor-like 27a CG59417-01 127 128 Ch otr sin recursor-like 28a CG59415-O1 129 130 Laminin t a EGF-like 28b 191815704 131 132 Laminin type EGF-like 28c 191815724 133 134 Laminin t a EGF-like 28d CG59415-02 135 136 Laminin t a EGF-like 29a CG59297-O1 137 138 Polycystic kidney disease 1 Protein-like 30a CG59264-O1 139 140 Polycystic kidney disease 2 Protein-like 31a CG59623-O1 141 142 Slit-like 32a CG59247-O1 143 144 Protein-tyrosine sulfotransferase-like 33a CG59430-O1 145 146 Serine Protease inhibitor-like 34a CG59305-O1 147 148 Fibronectin t a III-like 34b CG59305-02 149 150 Fibronectin t a III-like 35a CG59547-O1 151 152 Adipophilin-like 36a CG58508-Ol 153 154 Small inducible cytokine recursor -like 36b CG58508-02 155 156 Small inducible cytokine precursor -like 36c 170072532 157 158 Small inducible cytokine recursor -like 36d 170072551 159 160 Small inducible cytokine recursor -like 36e 170072555 161 162 Small inducible cytokine precursor -like 36f CG58508-03 163 164 Small inducible cytokine recursor -like 37a CG59819-O1 165 166 Latent transforming growth factor-like 37b CG59819-02 167 168 Latent transforming growth factor-like 37c CG59819-03 169 170 Latent transforming growth factor-like 38a CG59685-O1 171 172 Thrombos ondin-like 38b 175070296 173 174 Thrombos ondin-like 38c 175070324 175 176 Thrombos ondin-like 39a CG57167-O1 177 178 Urokinase plasminogen activator surface rece tor-like 40a CG59841-O1 179 180 Agrin recursor-like 41a CG59895-O1 181 182 Major urinary protein 4 precursor-like 41b CG59895-02 183 184 Major urinary protein 4 precursor-like 42a CG59889-O1 185 186 KIAAll99-like 42b CG59889-02 187 188 KIAA1199-like 42c CG59889-04 189 190 KIAA1199-like 43a CG59512-02 191 192 Small inducible c okine A3-like 43b CG59512-O1 193 194 Small inducible cytokine A3-like 44a CG56801-02 ~ 195 196 ~ Thrombomodulin-like ~

Table 1 indicates homology of NOVX nucleic acids to known protein families.
Thus, the nucleic acids and polypeptides, antibodies and related compounds according to the invention corresponding to a NOVX as identified in column 1 of Table 1 will be useful in therapeutic and diagnostic applications implicated in, for example, pathologies and disorders associated with the known protein families identified in column 5 of Table 1.
NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
Additionally, NOVX
nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.
Consistent with other known members of the family, of proteins, identified in column 5 of Table 1, the NOVX polypeptides of the present invention show homology to, and contain domains that are characteristic of, other members of such protein families.
Details of the sequence relatedness and domain analysis for each NOVX are presented in Examples 1-44.
The NOVX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVX activity or function. Specifically, the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit diseases associated with the protein families listed in Table 1.
The NOVX nucleic acids and polypeptides are also useful for detecting specific cell types. Details of the expression analysis for each NOVX are presented in Example 47.
Accordingly, the NOVX nucleic acids, polypeptides, antibodies and related compounds according to the invention will have diagnostic and therapeutic applications in the detection of a variety of diseases with differential expression in normal vs. diseased tissues, e.g.a variety of cancers.
Additional utilities for NOVX nucleic acids and polypeptides according to the invention are disclosed herein.
NOVX clones NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins.
Additionally, NOVX
nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.
The NOVX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy.
Pathological conditions can be diagnosed by determining the amount of the new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are described for each of the NOVX genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders.
The NOVX nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug'targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.
In one specific embodiment, the invention includes an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature foam are so changed; (c) an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 1 S% of the amino acid residues in the sequence are so changed; and (e) a fragment of any of (a) through (d).
In another specific embodiment, the invention includes an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 86; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:
2n, wherein n is an integer between 1 and 86 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86 or any variant of said polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and (f) the complement of any of said nucleic acid molecules.
In yet another specific embodiment, the invention includes an isolated nucleic acid molecule, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 86; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 86 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; (c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 86; and (d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 86 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed.
NOVX Nucleic Acids and Polypeptides One aspect of the invention pertains to isolated nucleic acid molecules that encode NOVX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify NOVX-encoding nucleic acids (e.g., NOVX mRNAs) and fragments for use as PCR primers for the amplification and/or mutation of NOVX nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double-stranded DNA.
A NOVX nucleic acid can encode a mature NOVX polypeptide. As used herein, a "mature" form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide, precursor form, or proprotein. The naturally occurnng polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product "mature" form arises, by way of nonlimiting example, as a result of one or more naturally occurnng processing steps that may take place within the cell (host cell) in which the gene product arises. Examples of such processing steps leading to a "mature" form of a polypeptide or protein include the cleavage of the N-terminal methionine residue encoded by the initiation codon of an ORF or the proteolytic cleavage of a signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N
remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+1 to residue N
remaining. Further as used herein, a "mature" form of a polypeptide or protein may arise from a post-translational modification other than a proteolytic cleavage event.
Such additional processes include, by way of non-limiting example, glycosylation, myristoylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them.
The term "probe", as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), and 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences.
Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single- or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies.
The term "isolated" nucleic acid molecule, as used herein, is a nucleic acid which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5'- and 3'-termini of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated NOVX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb, 0.1 kb, or less of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an "isolated"
nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, culture medium, or of chemical precursors or other chemicals.
A nucleic acid molecule of the invention, e.g., a nucleic acid molecule having the nucleotide sequence SEQ ID NOS: 2n-1, wherein n is an integer between 1 and 86, or a complement of this nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion of the nucleic acid sequence of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, as a hybridization probe, NOVX molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, et al., (eds.), MOLECULAR
CLONING: A
LABORATORY MANUAL 2°d Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausubel, et al., (eds.), CURRENT Ptto'rocot,s 11~1 MOLECULAR
BIOLOGY, John Wiley & Sons, New York, NY, 1993).

A nucleic acid of the invention can be amplified using cDNA, mRNA or, alternatively, genomic DNA as a template with appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.
As used herein, the term "oligonucleotide" refers to a series of linked nucleotide residues. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment of the invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes.
In another embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule that is a complement of the nucleotide sequence shown in SEQ ID
NOS:2n-1, wherein n is an integer between 1 and 86, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment encoding a biologically-active portion of A NOVX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence shown SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86,is one that is sufficiently complementary to the nucleotide sequence shown SEQ ID
NOS:2n-1, wherein n is an integer between 1 and 86,that it can hydrogen bond with few or no mismatches to the nucleotide sequence shown SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, thereby forming a stable duplex.
As used herein, the term "complementary" refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term "binding" means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct .
or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates.

"Fragments" provided herein are defined as sequences of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, and are at most some portion less than a full length sequence.
Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice.
A full-length NOVX clone is identified as containing an ATG translation start codon and an in-frame stop codon. Any disclosed NOVX nucleotide sequence lacking an ATG start codon therefore encodes a truncated C-terminal fragment of the respective NOVX
polypeptide, and requires that the corresponding full-length cDNA extend in the 5' direction of the disclosed sequence. Any disclosed NOVX nucleotide sequence lacking an in-frame stop codon similarly encodes a truncated N-terminal fragment of the respective NOVX
polypeptide, and requires that the corresponding full-length cDNA extend in the 3' direction of the disclosed sequence.
"Derivatives" are nucleic acid sequences or amino acid sequences formed from the native compounds either directly, by modification, or by partial substitution.
"Analogs" are nucleic acid sequences or amino acid sequences that have a structure similar to, but not identical to, the native compound, e.g. they differ from it in respect to certain components or side chains. Analogs may be synthetic or derived from a different evolutionary origin and may have a similar or opposite metabolic activity compared to wild type.
Homologs are nucleic acid sequences or amino acid sequences of a particular gene that are derived from different species.
Derivatives and analogs may be full length or other than full length.
Derivatives or analogs of the nucleic acids or proteins of the invention include, but are not limited to, molecules comprising regions that are substantially homologous to the nucleic acids or proteins of the invention, in various embodiments, by at least about 70%, 80%, or 95%
identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to the complement of a sequence encoding the proteins of the invention under stringent, moderately stringent, or low stringent conditions. See e.g.
Ausubel, et al., CURRENT
PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993, and below.
A "homologous nucleic acid sequence" or "homologous amino acid sequence," or variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences include those sequences coding for isoforms of NOVX polypeptides. Isoforms can be expressed in different tissues of the same organism as a result of, for example, alternative splicing of RNA.
Alternatively, isoforms can be encoded by different genes. In the invention, homologous nucleotide sequences include nucleotide sequences encoding for A NOVX
polypeptide of S species other than humans, including, but not limited to vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat, cow, horse, and other organisms.
Homologous nucleotide sequences also include, but are not limited to, naturally occurnng allelic variations and mutations of the nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding a human NOVX
protein.
Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NOS:2n-l, wherein n is an integer between 1 and 86, as well as a polypeptide possessing NOVX biological activity.
Various biological activities of the NOVX proteins are described below.
A NOVX polypeptide is encoded by the open reading frame ("ORF") of a NOVX
nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG
"start" codon and terminates with one of the three "stop" codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bona fide cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more.
The nucleotide sequences determined from the cloning of the human NOVX genes allows for the generation of probes and primers designed for use in identifying and/or cloning NOVX homologues in other cell types, e.g. from other tissues, as well as NOVX
homologues from other vertebrates. The probe/primer typically comprises a substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, S0, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86; or an anti-sense strand nucleotide sequence of SEQ
ID NOS:2n-1, wherein n is an integer between 1 and 86; or of a naturally occurring mutant of SEQ ID
NOS:2n-l, wherein n is an integer between 1 and 86.
Probes based on the human NOVX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe has a detectable label attached, e.g. the label can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis-express A
NOVX protein, such as by measuring a level of A NOVX-encoding nucleic acid in a sample of cells from a subject e.g., detecting NOVX mIRNA levels or determining whether a genomic NOVX gene has been mutated or deleted.
"A polypeptide having a biologically-active portion of A NOVX polypeptide"
refers to polypeptides exhibiting activity similar, but not necessarily identical, an activity of a polypeptide of the invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a "biologically-active portion of NOVX" can be prepared by isolating a portion SEQ ID NOS:2n-l, wherein n is an integer between 1 and 86, that encodes a polypeptide having A NOVX
biological activity (the biological activities of the NOVX proteins are described below), expressing the encoded portion of NOVX protein (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of NOVX.
NOVX Nucleic Acid and Polypeptide Variants The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences shown in SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, due to degeneracy of the genetic code and thus encode the same NOVX proteins as that encoded by the nucleotide sequences shown in SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence shown in SEQ
ID NOS:2n, wherein n is an integer between 1 and 86.
In addition to the human NOVX nucleotide sequences shown in SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of the NOVX
polypeptides may exist within a population (e.g., the human population). Such genetic polymorphism in the NOVX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame (O1RF') encoding A
NOVX protein, preferably a vertebrate NOVX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the NOVX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the NOVX polypeptides, which are the result of natural allelic variation and that do not alter the functional activity of the NOVX
polypeptides, are intended to be within the scope of the invention.
Moreover, nucleic acid molecules encoding NOVX proteins from other species, and thus that have a nucleotide sequence that differs from the human SEQ ID NOS:2n-1, wherein S n is an integer between 1 and 86, are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the NOVX cDNAs of the invention can be isolated based on their homology to the human NOVX
nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.
Accordingly, in another embodiment, an isolated nucleic acid molecule of the invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule of the invention hybridizes to the coding region. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least about 65% homologous to each other typically remain hybridized to each other.
Homologs (i.e., nucleic acids encoding NOVX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion of the particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning.
As used herein, the phrase "stringent hybridization conditions" refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5 °C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess at Tm, 50% of the probes are occupied at equilibrium. Typically, stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M
sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30 °C for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60 °C for longer probes, primers and oligonucleotides. Stringent conditions may also be achieved with the addition of destabilizing agents, such as fonmamide.
Stringent conditions are known to those skilled in the art and can be found in Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N.Y.
(1989), 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6X SSC, 50 mM Tris-HCl (pH
7.5), 1 mM
EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA
at 65 °C, followed by one or more washes in 0.2X SSC, 0.01% BSA at 50 °C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to the sequences SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, corresponds to a naturally-occurring nucleic acid molecule. As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).
In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6X SSC, SX Denhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55 °C, followed by one or more washes in 1X SSC, 0.1% SDS at 37 °C. Other conditions of moderate stringency that may be used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT
PROTOCOLS IN
MOLECULAR B10LOGY, John Wiley & Sons, NY, and Kriegler, 1990; GENE TRANSFER
AND
EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY.
In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, SX SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02%
PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmon sperm DNA, 10%
(wt/vol) dextran sulfate at 40 °C, followed by one or more washes in 2X SSC, 25 mM Tris-HCI (pH

7.4), 5 mM EDTA, and 0.1 % SDS at 50 °C. Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley &
Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY
MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. Proc Natl Acad Sci USA 78: 6789-6792.
Conservative Mutations In addition to naturally-occurring allelic variants of NOVX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences SEQ ID NOS:2n-l, wherein n is an integer between 1 and 86, thereby leading to changes in the amino acid sequences of the encoded NOVX
proteins, without altering the functional ability of the NOVX proteins. For example, nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues can be made in the sequence SEQ ID NOS:2n, wherein n is an integer between 1 and 86. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequences of the NOVX proteins without altering their biological activity, whereas an "essential" amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the NOVX proteins of the invention are predicted to be particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well known within the art.
Another aspect of the invention pertains to nucleic acid molecules encoding NOVX
proteins that contain changes in amino acid residues that are not essential for activity. Such NOVX proteins differ in amino acid sequence from SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 45% homologous to the amino acid sequences SEQ ID NOS:2n, wherein n is an integer between 1 and 86. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ
ID NOS:2n, wherein n is an integer between 1 and 86; more preferably at least about 70%
homologous SEQ ID NOS:2n, wherein n is an integer between 1 and 86; still more preferably at least about 80% homologous to SEQ ID NOS:2n, wherein n is an integer between 1 and 86;
even more preferably at least about 90% homologous to SEQ ID NOS:2n, wherein n is an integer between 1 and 86; and most preferably at least about 95% homologous to SEQ ID
NOS:2n, wherein n is an integer between 1 and 86.

An isolated nucleic acid molecule encoding A NOVX protein homologous to the protein of SEQ ID NOS:2n, wherein n is an integer between 1 and 86, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NOS:2n-l, wherein n is an integer between 1 and 86, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein.
Mutations can be introduced into SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted, non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., asparric acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side I S chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the NOVX protein is replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of A NOVX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for NOVX biological activity to identify mutants that retain activity. Following mutagenesis SEQ ID NOS:2n-1, wherein n is an integer between I and 86, the encoded protein can be expressed by any recombinant technology known in the art and the activity of the protein can be determined.
The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved "strong" residues or fully conserved "weak" residues. The "strong" group of conserved amino acid residues may be any one of the following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the "weak" group of conserved residues may be any one of the following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, HFY, wherein the letters within each group represent the single letter amino acid code.
In one embodiment, a mutant NOVX protein can be assayed for (i) the ability to form protein:protein interactions with other NOVX proteins, other cell-surface proteins, or biologically-active portions thereof, (ii) complex formation between a mutant NOVX protein and A NOVX ligand; or (iii) the ability of a mutant NOVX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins).
In yet another embodiment, a mutant NOVX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release).
Antisense Nucleic Acids Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, or fragments, analogs or derivatives thereof. An "antisense" nucleic acid comprises a nucleotide sequence that is complementary to a "sense" nucleic acid encoding a protein (e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire NOVX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of A NOVX protein of SEQ
ID
NOS:2n, wherein n is an integer between 1 and 86, or antisense nucleic acids complementary to A NOVX nucleic acid sequence of SEQ ID NOS:2n-l, wherein n is an integer between 1 and 86, are additionally provided.
In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence encoding A NOVX protein.
The term "coding region" refers to the region of the nucleotide sequence comprising codons, which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence encoding the NOVX protein. The term "noncoding region" refers to S' and 3' sequences, which flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions).
Given the coding strand sequences encoding the NOVX protein disclosed herein, antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of NOVX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of NOVX mltNA.
For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of NOVX mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used).
Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.
Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA
transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).
The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding A NOVX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.
In yet another embodiment, the antisense nucleic acid molecule of the invention is an a-anomeric nucleic acid molecule. A a-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual (3-units, the strands run parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl.
Acids Res. 15:
6625-6641. The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (See, e.g., moue, et al. 1987. Nucl. Acids Res. 15:
6131-6148) or a chimeric RNA-DNA analogue (See, e.g., moue, et al., 1987. FEBS Lett. 215: 327-330.
Ribozymes and PNA Moieties Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized.
These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.
In one embodiment, an antisense nucleic acid of the invention is a ribozyme.
Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in Haselhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave NOVX
mRNA transcripts to thereby inhibit translation of NOVX mRNA. A ribozyme having specificity for a NOVX-encoding nucleic acid can be designed based upon the nucleotide sequence of A NOVX cDNA disclosed herein (i.e., SEQ ID NOS:2n-l, wherein n is an integer between 1 and 86). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a NOVX-encoding mRNA. See, e.g., U.S.
Patent 4,987,071 to Cech, et al. and U.S. Patent 5,116,742 to Cech, et al. NOVX mRNA
can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA
molecules. See, e.g., Bartel et al., (1993) Science 261:1411-1418.
Alternatively, NOVX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the NOVX nucleic acid (e.g., the NOVX
S promoter and/or enhancers) to form triple helical structures that prevent transcription of the NOVX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6:
569-84; Helene, et al. 1992. Ann. N. Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15.
In various embodiments, the NOVX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al., 1996.
Bioorg Med Chem 4: 5-23. As used herein, the terms "peptide nucleic acids" or "PNAs"
refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained.
The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al., 1996. supra;
Pent'-O'Keefe, et al., 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675.
PNAs of NOVX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of NOVX can also be used, for example, in the analysis of single base pair mutations in a gene (e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S~ nucleases (See, Hyrup, et al., 1996.supra); or as probes or primers for DNA sequence and hybridization (See, Hyrup, et al., 1996, supra; Perry-0'Keefe, et al., 1996. supra).
In another embodiment, PNAs of NOVX can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras of NOVX can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA
recognition enzymes (e.g., RNase H and DNA polymerases) to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA
chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (see, Hyrup, et al., 1996. supra).
The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al., 1996.
supra and Finn, et al., 1996. Nucl Acids Res 24: 3357-3363. For example, a DNA
chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5' end of DNA. See, e.g., Mag, et al., 1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment.
See, e.g., Finn, et al., 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5' DNA
segment and a 3' PNA segment. See, e.g., Petersen, et al., 1975. Bioorg. Med.
Chem. Lett. 5:
1119-11124.
In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger, et al., 1989. Proc. Natl. Acad. Sci.
U.S.A. 86:
6553-6556; Lemaitre, et al., 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT
Publication No.
W088/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO
89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al., 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988.
Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, and the like.
NOVX Polypeptides A polypeptide according to the invention includes a polypeptide including the amino acid sequence of NOVX polypeptides whose sequences are provided in SEQ ID
NOS:2n, wherein n is an integer between 1 and 86. The invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residues shown in SEQ
ID NOS:2n, wherein n is an integer between 1 and 86, while still encoding a protein that maintains its NOVX activities and physiological functions, or a functional fragment thereof.
In general, A NOVX variant that preserves NOVX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues of the parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above.
One aspect of the invention pertains to isolated NOVX proteins, and biologically-active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-NOVX
antibodies. In one embodiment, native NOVX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, NOVX proteins are produced by recombinant DNA techniques.
Alternative to recombinant expression, A NOVX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques.
An "isolated" or "purified" polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the NOVX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of NOVX proteins in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly-produced. In one embodiment, the language "substantially free of cellular material"
includes preparations of NOVX proteins having less than about 30% (by dry weight) of non-NOVX proteins (also referred to herein as a "contaminating protein"), more preferably less than about 20% of a non-NOVX proteins, still more preferably less than about 10% of non-NOVX
proteins, and most preferably less than about 5% of non-NOVX proteins. When the NOVX protein or biologically-active portion thereof is recombinantly-produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the NOVX protein preparation.
The language "substantially free of chemical precursors or other chemicals"
includes preparations of NOVX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis of the protein. In one embodiment, the language "substantially free of chemical precursors or other chemicals"
includes preparations of NOVX proteins having less than about 30% (by dry weight) of chemical precursors or non-NOVX chemicals, more preferably less than about 20% chemical precursors or non-NOVX chemicals, still more preferably less than about 10% chemical precursors or non-NOVX chemicals, and most preferably less than about 5% chemical precursors or non-NOVX chemicals.

Biologically-active portions of NOVX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the NOVX proteins (e.g., the amino acid sequence shown in SEQ ID NOS:2n, wherein n is an integer between 1 and 86) that include fewer amino acids than the full-length NOVX proteins, and exhibit at least one activity of A NOVX protein. Typically, biologically-active portions comprise a domain or motif with at least one activity of the NOVX protein. A
biologically-active portion of A NOVX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length.
Moreover, other biologically-active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of a native NOVX protein.
In an embodiment, the NOVX protein has an amino acid sequence shown SEQ ID
NOS:2n, wherein n is an integer between 1 and 86. In other embodiments, the NOVX protein is substantially homologous to SEQ ID NOS:2n, wherein n is an integer between 1 and 86, and retains the functional activity of the protein of SEQ ID NOS:2n, wherein n is an integer between 1 and 86, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the NOVX
protein is a protein that comprises an amino acid sequence at least about 45%
homologous to the amino acid sequence SEQ ID NOS:2n, wherein n is an integer between 1 and 86, and retains the functional activity of the NOVX proteins of SEQ ID NOS:2n, wherein n is an integer between 1 and 86.
DETERMINING HOMOLOGY BETWEEN TWO OR MORE SEQUENCES
To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared.
When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid "homology" is equivalent to amino acid or nucleic acid "identity").
The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. .l Mol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP
extension penalty of 0.3, the coding region of the analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA sequence shown in SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86.
The term "sequence identity" refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i. e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term "substantial identity" as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region.

The invention also provides NOVX chimeric or fusion proteins. As used herein, A
NOVX "chimeric protein" or "fusion protein" comprises A NOVX polypeptide operatively-linked to a non-NOVX polypeptide. An "NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to A NOVX protein SEQ ID NOS:2n, wherein n is an integer between 1 and 86, whereas a "non-NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the NOVX protein, e.g., a protein that is different from the NOVX protein and that is derived from the same or a different organism. Within A NOVX fusion protein the NOVX
polypeptide can correspond to all or a portion of A NOVX protein. In one embodiment, A NOVX
fusion protein comprises at least one biologically active portion of A NOVX protein.
In another embodiment, A NOVX fusion protein comprises at least two biologically active portions of A
NOVX protein. In yet another embodiment, A NOVX fusion protein comprises at least three Biologically-active portions of NOV

biologically active portions of A NOVX protein. Within the fusion protein, the term "operatively-linked" is intended to indicate that the NOVX polypeptide and the non-NOVX
polypeptide are fused in-frame with one another. The non-NOVX polypeptide can be fused to the N-terminus or C-terminus of the NOVX polypeptide.
In one embodiment, the fusion protein is a GST-NOVX fusion protein in which the NOVX sequences are fused to the C-terminus of the GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant NOVX
polypeptides.
In another embodiment, the fusion protein is A NOVX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of NOVX can be increased through use of a heterologous signal sequence.
In yet another embodiment, the fusion protein is a NOVX-immunoglobulin fusion protein in which the NOVX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The NOVX-immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between A NOVX ligand and A NOVX protein on the surface of a cell, to thereby suppress NOVX-mediated signal transduction in vivo. The NOVX-immunoglobulin fusion proteins can be used to affect the bioavailability of A NOVX cognate ligand. Inhibition of the NOVX ligand/NOVX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g.
promoting or inhibiting) cell survival. Moreover, the NOVX-immunoglobulin fusion proteins of the invention can be used as immunogens to produce anti-NOVX antibodies in a subject, to purify NOVX ligands, and in screening assays to identify molecules that inhibit the interaction of NOVX with A
NOVX ligand.
A NOVX chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carned out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel, et al. (eds.) CURRENT PROTOCOLS IN
MOLECULAR
BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A
NOVX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the NOVX protein.
NOVX AGONISTS AND ANTAGONISTS
The invention also pertains to variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists. Variants of the NOVX
protein can be generated by mutagenesis (e.g., discrete point mutation or truncation of the NOVX protein).
An agonist of the NOVX protein can retain substantially the same, or a subset of, the biological activities of the naturally occurnng form of the NOVX protein. An antagonist of the NOVX protein can inhibit one or more of the activities of the naturally occurring form of the NOVX protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade, which includes the NOVX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the NOVX proteins.
Variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists can be identified by screening combinatorial libraries of mutants (e.g., truncation mutants) of the NOVX proteins for NOVX protein agonist or antagonist activity. In one embodiment, a variegated library of NOVX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of NOVX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential NOVX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of NOVX sequences therein. There are a variety of methods, which can be used to produce libraries of potential NOVX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA
synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential NOVX sequences. Methods for synthesizing degenerate oligonucleotides are well known within the art. See, e.g., Narang, 1983.
Tetrahedron 39: 3;
Itakura, et al., 1984. Annu. Rev. Biochem. 53: 323; Itakura, et al., 1984.
Science 198: 1056;
Ike, et al., 1983. Nucl. Acids Res. 11: 477.
POLY PEPTIDE LIBRARIES
In addition, libraries of fragments of the NOVX protein coding sequences can be used to generate a variegated population of NOVX fragments for screening and subsequent selection of variants of A NOVX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of A
NOVX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with S~ nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal and internal fragments of various sizes of the NOVX
proteins.
Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA
libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of NOVX proteins.
The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected.
Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify NOVX variants.
See, e.g., Arkin and Yourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 7811-7815;
Delgrave, et al., 1993. Protein Engineering 6:327-331.
NOVX Antibodies The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, Fab~ and F~ab~~z fragments, and an Fab expression library. In general, antibody molecules obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule.
Certain classes have subclasses as well, such as IgG,, IgGz, and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.
An isolated protein of the invention intended to serve as an antigen, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein, such as an amino acid sequence shown in SEQ ID NOs: 2n, wherein n is an integer between 1 and 86, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.
In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a region of NOVX that is located on the surface of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human NOVX protein sequence will indicate which regions of a NOVX polypeptide are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78:
3824-3828;
Kyte and Doolittle 1982, J. Mol. Biol. 157: 105-142, each incorporated herein by reference in their entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.

A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.
Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, incorporated herein by reference). Some of these antibodies are discussed below.
Polyclonal Antibodies For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized.
Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents.
Additional examples of adjuvants which can be employed include MPL-TDM
adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).
The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol. 14, No. 8 (April 17, 2000), pp. 25-28).
Monoclonal Antibodies The term "monoclonal antibody" (MAb) or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population.
MAbs thus contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.
Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro.
The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell [coding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103]. Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT
medium"), which substances prevent the growth of HGPRT-deficient cells.
Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63].
The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen.
Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980).
It is an objective, especially important in therapeutic applications of monoclonal antibodies, to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen.
After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods (Goding,l986).
Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.
The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells.
The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.5.
Patent No.
4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.
Humanized Antibodies The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin.
Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988);
Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Patent No.
5,225,539.) In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences.
In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. On.
Struct. Biol., 2:593-596 (1992)).
Human Antibodies Fully human antibodies essentially relate to antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies", or "fully human antibodies" herein.

Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV
hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In:
MONOCLONAL
ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80:
2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cele, et al., 1985 In:
MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).
In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991);
Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated.
Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806;
5,569,825;
5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Technolo~y 10, 779-783 (1992));
Lonberg et al. (Nature 368 856-859 (1994)); Morrison ( Nature 368, 812-13 (1994)); Fishwild et al,( Nature Biotechnolo~v 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93 (1995)).
Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT
publication W094/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the XenomouseTM as disclosed in PCT publications WO
96/33735 and 6. This animal produces B cells which secrete fully human immunoglobulins.
The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.
An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Patent No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.
A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Patent No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell.
The hybrid cell expresses an antibody containing the heavy chain and the light chain.
In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT
publication WO 99/53049.
Fab Fragments and Single Chain Antibodies According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Patent No. 4,946,778). In addition, methods can be adapted for the construction of Fab expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F~ab')2 fragment produced by pepsin digestion of an antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F~ab')2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) F~ fragments.
Bispecific Antibodies Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.
Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO
93/08829, published 13 May 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).
Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).
According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chains) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine).
This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.
Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab')Z bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab')Z fragments.
These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation.
The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives.
One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB
derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.
Additionally, Fab' fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab')2 molecule. Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.
Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol.
148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers.
This method can also be utilized for the production of antibody homodimers.
The "diabody"
technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments.
The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (V~) by a linker which is too short to allow pairing between the two domains on the same chain.
Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994).
Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).
Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcyR), such as FcyRI (CD64), FcyRII (CD32) and FcyRIII
(CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).
Heteroconjugate Antibodies Heteroconjugate antibodies are also within the scope of the present invention.
Heteroconjugate antibodies are composed of two covalently joined antibodies.
Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Patent No. 4,676,980), and for treatment of HIV infection (WO 91/00360;
WO
92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents.
For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S.
Patent No.
4,676,980.
Effector Function Engineering It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residues) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Ex~
Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993).
Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Dru Designn, 3: 219-230 (1989).
Immunoconjugates The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).
Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies.
Examples include Zl2Bi, ~3~I, l3~In, 9oY, and ~86Re.
Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026.
In another embodiment, the antibody can be conjugated to a "receptor" (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand" (e.g., avidin) that is in turn conjugated to a cytotoxic agent.
Immunoliposomes The antibodies disclosed herein can also be formulated as immunoliposomes.
Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985);
Hwang et al., Proc.
Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545.
Liposomes with enhanced circulation time are disclosed in U.S. Patent No.
5,013,556.
Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al ., J.
Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A
chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon et al., J.
National Cancer Inst., 81(19): 1484 (1989).
Diagnostic Applications of Antibodies Directed Against the Proteins of the Invention Antibodies directed against a protein of the invention may be used in methods known within the art relating to the localization and/or quantitation of the protein (e.g., for use in measuring levels of the protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies against the proteins, or derivatives, fragments, analogs or homologs thereof, that contain the antigen binding domain, are utilized as pharmacologically-active compounds (see below).
An antibody specific for a protein of the invention can be used to isolate the protein by standard techniques, such as immunoaffinity chromatography or immunoprecipitation. Such an antibody can facilitate the purification of the natural protein antigen from cells and of recombinantly produced antigen expressed in host cells. Moreover, such an antibody can be used to detect the antigenic protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the antigenic protein.
Antibodies directed against the protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, ~i-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include l2sh 131I' 35s or 3H.
Antibody Therapeutics Antibodies of the invention, including polyclonal, monoclonal, humanized and fully human antibodies, may used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Such an effect may be one of two kinds, depending on the specific nature of the interaction between the given antibody molecule and the target antigen in question. In the first instance, administration of the antibody may abrogate or inhibit the binding of the target with an endogenous ligand to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, wherein the ligand serves as an effector molecule.
Thus the receptor mediates a signal transduction pathway for which ligand is responsible.
Alternatively, the effect may be one in which the antibody elicits a physiological result by virtue of binding to an effector binding site on the target molecule. In this case the target, a receptor having an endogenous ligand which may be absent or defective in the disease or pathology, binds the antibody as a surrogate effector ligand, initiating a receptor-based signal transduction event by the receptor.
A therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target, and in other cases, promotes a physiological response. The amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered.
Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about SO
mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week.
Pharmaceutical Compositions of Antibodies Antibodies specifically binding a protein of the invention, as well as other molecules identified by the screening assays disclosed herein, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington : The Science And Practice Of Pharmacy 19th ed.
1 S (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa. : 1995;
Drug Absorption Enhancement : Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York.
If the antigenic protein is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA
technology.
See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993).
The formulation herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.
The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.
Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat.
No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON
DEPOT ~ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.
ELISA Assay An agent for detecting an analyte protein is an antibody capable of binding to an analyte protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F~ab)z) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i. e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term "biological sample", therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph.
That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mIRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for example in "ELISA: Theory and Practice: Methods in Molecular Biology", Vol. 42, J. R.
Crowther (Ed.) Human Press, Totowa, NJ, 1995; "Immunoassay", E. Diamandis and T.
Christopoulus, Academic Press, Inc., San Diego, CA, 1996; and "Practice and Thory of Enzyme Immunoassays", P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985.
Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-an analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.
NOVX Recombinant Expression Vectors and Host Cells Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding A NOVX protein, or derivatives, fragments, analogs or homologs thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA
segments can be ligated. Another type of vector is a viral vector, wherein additional DNA
segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome.
Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids.
In the present specification, "plasmid" and "vector" can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably-linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequences) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).
The term "regulatory sequence" is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN
ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., NOVX
proteins, mutant forms of NOVX proteins, fusion proteins, etc.).
The recombinant expression vectors of the invention can be designed for expression of NOVX proteins in prokaryotic or eukaryotic cells. For example, NOVX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Cali~ (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.
Expression of proteins in prokaryotes is most often carned out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (iii) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL
(New England Biolabs, Beverly, Mass.) and pRITS (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.
Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al., (1988) Gene 69:301-315) and pET l 1d (Studier et al., GENE
EXPRESSION
TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Cali~ (1990) 60-89).
One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN
ENZYMOLOGY
185, Academic Press, San Diego, Cali~ (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E.
coli (see, e.g., Wada, et al., 1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques.
In another embodiment, the NOVX expression vector is a yeast expression vector.
Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSec 1 (Baldari, et al., 1987. EMBO J. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30:
933-943), pJRY88 (Schultz et al., 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Cali~), and picZ (InVitrogen Corp, San Diego, Cali~).
Alternatively, NOVX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3:
2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).
In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987.
EMBO
J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.
In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid).
Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987.
Genes Dev. 1:
268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol.
43:
235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J.
8: 729-733) and immunoglobulins (Banerji, et al., 1983. Cell 33: 729-740;
Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the a-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546).
The invention further provides a recombinant expression vector comprising a DNA
molecule of the invention cloned into the expression vector in an antisense orientation. 'That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to NOVX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA
molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub, et al., "Antisense RNA
as a molecular tool for genetic analysis," Reviews-Trends in Genetics, Vol. 1(1) 1986.

Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms "host cell"
and "recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.
A host cell can be any prokaryotic or eukaryotic cell. For example, NOVX
protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.
Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.
For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as 6418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding NOVX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).
A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) NOVX protein. Accordingly, the invention further provides methods for producing NOVX protein using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding NOVX protein has been introduced) in a suitable medium such that NOVX protein is produced. In another embodiment, the method further comprises isolating NOVX protein from the medium or the host cell.
Transgenic NOVX Animals The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which NOVX protein-coding sequences have been introduced.
Such host cells can then be used to create non-human transgenic animals in which exogenous NOVX sequences have been introduced into their genome or homologous recombinant animals in which endogenous NOVX sequences have been altered. Such animals are useful for studying the function and/or activity of NOVX protein and for identifying and/or evaluating modulators of NOVX protein activity. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in E
which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous NOVX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.
A transgenic animal of the invention can be created by introducing NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human NOVX cDNA sequences SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, can be introduced as a transgene into the genome of a non-human animal.
Alternatively, a non-human homologue of the human NOVX gene, such as a mouse NOVX gene, can be isolated based on hybridization to the human NOVX cDNA (described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequences) can be operably-linked to the NOVX transgene to direct expression of NOVX protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Patent Nos.
4,736,866;
4,870,009; and 4,873,191; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold S Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the NOVX transgene in its genome and/or expression of NOVX mRNA
in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding NOVX protein can further be bred to other transgenic animals carrying other transgenes.
To create a homologous recombinant animal, a vector is prepared which contains at least a portion of A NOVX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the NOVX gene. The NOVX gene can be a human gene (e.g., the cDNA of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86), but more preferably, is a non-human homologue of a human NOVX gene. For example, a mouse homologue of human NOVX gene of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous recombination, the endogenous NOVX gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a "knock out" vector).
Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous NOVX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous NOVX protein). In the homologous recombination vector, the altered portion of the NOVX gene is flanked at its S'- and 3'-termini by additional nucleic acid of the NOVX
gene to allow for homologous recombination to occur between the exogenous NOVX
gene carried by the vector and an endogenous NOVX gene in an embryonic stem cell.
The additional flanking NOVX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5'- and 3'-termini) are included in the vector. See, e.g., Thomas, et al., 1987. Cell 51:
503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced NOVX

gene has homologously-recombined with the endogenous NOVX gene are selected.
See, e.g., Li, et al., 1992. Cell 69: 915.
The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND
EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp.
113-152.
A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously-recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously-recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol. 2: 823-829; PCT
International Publication Nos.: WO 90/11354; WO 91/01140; WO 92/0968; and WO 93/04169.
In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P 1. For a description of the cre/loxP recombinase system, See, e.g., Lakso, et al., 1992. Proc. Natl. Acad.
Sci. USA 89:
6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al., 1991. Science 251:1351-1355.
If a cre/loxP
recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.
Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al., 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter Go phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone of the animal from which the cell (e.g., the somatic cell) is isolated.

Pharmaceutical Compositions The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVX antibodies (also referred to herein as "active compounds") of the invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable Garners are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such Garners or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and S%
human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be 1 S used. 'The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components:
a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfate;
chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL~' (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound (e.g., A NOVX protein or anti-NOVX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Oral compositions generally include an inert diluent or an edible carrier.
They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable Garners. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S.
Patent No. 4,522,811.
It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated;
each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
The nucleic acid molecules of the invention can be inserted into vectors and used as S gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Patent No.
5,328,470) or by stereotactic injection (see, e.g., Chen, et al., 1994. Proc. Natl. Acad. Sci.
USA 91: 3054-3057).
The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system.
The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
Screening and Detection Methods The isolated nucleic acid molecules of the invention can be used to express NOVX
protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect NOVX mIRNA (e.g., in a biological sample) or a genetic lesion in A
NOVX gene, and to modulate NOVX activity, as described further, below. In addition, the NOVX proteins can be used to screen drugs or compounds that modulate the NOVX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of NOVX protein or production of NOVX protein forms that have decreased or aberrant activity compared to NOVX wild-type protein (e.g.; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease(possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-NOVX antibodies of the invention can be used to detect and isolate NOVX proteins and modulate NOVX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in both a positive and negative fashion.
The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra.

Screening Assays The invention provides a method (also referred to herein as a "screening assay") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to NOVX proteins or have a stimulatory or inhibitory effect on, e.g., NOVX protein expression or NOVX
protein activity.
The invention also includes compounds identified in the screening assays described herein.
In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of the membrane-bound form of A NOVX
protein or polypeptide or biologically-active portion thereof. The test compounds of the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound" library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12: 145.
A "small molecule" as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention.
Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al., 1993. Proc. Natl. Acad. Sci. U.S.A. 90: 6909;
Erb, et al., 1994.
Proc. Natl. Acad. Sci. U.S.A. 91: 11422; Zuckermann, et al., 1994. J. Med.
Chem. 37: 2678;
Cho, et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem. Int.
Ed. Engl. 33:
2059; Carell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2061; and Gallop, et al., 1994. J.
Med. Chem. 37: 1233.
Libraries of compounds may be presented in solution (e.g., Houghten, 1992.
Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Patent No. 5,223,409), spores (Ladner, U.S. Patent 5,233,409), plasmids (Cull, et al., 1992. Proc. Natl. Acad. Sci.
USA 89:
1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991.
J. Mol. Biol. 222: 301-310; Ladner, U.S. Patent No. 5,233,409.).
In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface is contacted with a test compound and the ability of the test compound to bind to A
NOVX protein determined. The cell, for example, can of mammalian origin or a yeast cell.
Determining the ability of the test compound to bind to the NOVX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the NOVX protein or biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with ~zsl, 3s5, laC, or 3H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting.
Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with A NOVX
protein, wherein determining the ability of the test compound to interact with A NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX
protein or a biologically-active portion thereof as compared to the known compound.
In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX or a biologically-active portion thereof can be accomplished, for example, by determining the ability of the NOVX protein to bind to or interact with A NOVX
target molecule. As used herein, a "target molecule" is a molecule with which A NOVX
protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses A
NOVX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule. A NOVX target molecule can be a non-NOVX molecule or A
NOVX

protein or polypeptide of the invention. In one embodiment, A NOVX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound NOVX
molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with NOVX.
Determining the ability of the NOVX protein to bind to or interact with A NOVX
target molecule can be accomplished by one of the methods described above for determining direct binding. In one embodiment, determining the ability of the NOVX protein to bind to or interact with A NOVX target molecule can be accomplished by determining the activity of the target molecule. For example, the activity of the target molecule can be determined by detecting induction of a cellular second messenger of the target (i.e.
intracellular Caz+, diacylglycerol, IP3, etc.), detecting catalytic/enzymatic activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising A NOVX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.
In yet another embodiment, an assay of the invention is a cell-free assay comprising contacting A NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to bind to the NOVX protein or biologically-active portion thereof. Binding of the test compound to the NOVX protein can be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with A
NOVX protein, wherein determining the ability of the test compound to interact with A NOVX
protein comprises determining the ability of the test compound to preferentially bind to NOVX or biologically-active portion thereof as compared to the known compound.
In still another embodiment, an assay is a cell-free assay comprising contacting NOVX
protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to modulate (e.g. stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX can be accomplished, for example, by determining the ability of the NOVX protein to bind to A NOVX target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of NOVX protein can be accomplished by determining the ability of the NOVX protein further modulate A NOVX target molecule. For example, the catalytic/enzymatic activity of the target molecule on an appropriate substrate can be determined as described, supra.
In yet another embodiment, the cell-free assay comprises contacting the NOVX
protein or biologically-active portion thereof with a known compound which binds NOVX
protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with A NOVX protein, wherein determining the ability of the test compound to interact with A NOVX protein comprises determining the ability of the NOVX protein to preferentially bind to or modulate the activity of A NOVX
target molecule.
The cell-free assays of the invention are amenable to use of both the soluble form or the membrane-bound form of NOVX protein. In the case of cell-free assays comprising the membrane-bound form of NOVX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of NOVX protein is maintained in solution.
Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton~ X-100, Triton~ X-114, Thesit~, Isotridecypoly(ethylene glycol ether)", N-dodecyl--N,N-dimethyl-3-ammonio-1-propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1-propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate (CHAPSO).
In more than one embodiment of the above assay methods of the invention, it may be desirable to immobilize either NOVX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Binding of a test compound to NOVX protein, or interaction of NOVX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants.
Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, GST-NOVX fusion proteins or GST-target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or NOVX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra.
Alternatively, the complexes can be dissociated from the matrix, and the level of NOVX protein binding or activity determined using standard techniques.
Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either the NOVX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin.
Biotinylated NOVX protein or target molecules can be prepared from biotin-NHS
(N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with NOVX protein or target molecules, but which do not interfere with binding of the NOVX protein to its target molecule, can be derivatized to the wells of the plate, and unbound target or NOVX
protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the NOVX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the NOVX
protein or target molecule.
In another embodiment, modulators of NOVX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of NOVX
mRNA or protein in the cell is determined. The level of expression of NOVX
mRNA or protein in the presence of the candidate compound is compared to the level of expression of NOVX mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of NOVX mRNA or protein expression based upon this comparison. For example, when expression of NOVX mRNA or protein is greater (i.e., statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of NOVX mRNA or protein expression. Alternatively, when expression of NOVX mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of NOVX mRNA or protein expression. The level of NOVX mRNA or protein expression in the cells can be determined by methods described herein for detecting NOVX mRNA or protein.

In yet another aspect of the invention, the NOVX proteins can be used as "bait proteins" in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Patent No. 5,283,317;
Zervos, et al., 1993. Cell 72: 223-232; Madura, et al., 1993. J. Biol. Chem.
268: 12046-12054;
Bartel, et al., 1993. Biotechniques 14: 920-924; Iwabuchi, et al., 1993.
Oncogene 8:
1693-1696; and Brent WO 94/10300), to identify other proteins that bind to or interact with NOVX ("NOVX-binding proteins" or "NOVX-by") and modulate NOVX activity. Such NOVX-binding proteins are also likely to be involved in the propagation of signals by the NOVX proteins as, for example, upstream or downstream elements of the NOVX
pathway.
The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for NOVX
is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation 1 S domain of the known transcription factor. If the "bait" and the "prey"
proteins are able to interact, in vivo, forming A NOVX-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with NOVX.
The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein.
Detection Assays Portions or fragments of the cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (ii) identify an individual from a minute biological sample (tissue typing); and (iii) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below.

Chromosome Mapping Once the sequence (or a portion of the sequence) of a gene has been isolated, this sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments of the NOVX sequences, SEQ ID
NOS:2n-1, wherein n is an integer between 1 and 86, or fragments or derivatives thereof, can be used to map the location of the NOVX genes, respectively, on a chromosome.
The mapping of the NOVX sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease.
Briefly, NOVX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 by in length) from the NOVX sequences. Computer analysis of the NOVX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the NOVX sequences will yield an amplified fragment.
Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et al., 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions.
PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycler. Using the NOVX sequences to design oligonucleotide primers, sub-localization can be achieved with panels of fragments from specific chromosomes.
Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually.
The FISH technique can be used with a DNA sequence as short as S00 or 600 bases.
However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection.
Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al., HUMAN
CHROMOSOMES: A
1 O MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988).
Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more 1 S likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.
Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line 20 through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, et al., 1987.
Nature, 325: 783-787.
Moreover, differences in the DNA sequences between individuals affected and 25 unaffected with a disease associated with the NOVX gene, can be determined.
If a mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease.
Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible from chromosome 30 spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms.

Tissue Typing The NOVX sequences of the invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences of the invention are useful as additional DNA
markers for RFLP
("restriction fragment length polymorphisms," described in U.S. Patent No.
5,272,057).
Furthermore, the sequences of the invention cari be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the NOVX sequences described herein can be used to prepare two PCR primers from the 5'- and 3'-termini of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it.
Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences of the invention can be used to obtain such identification sequences from individuals and from tissue. The NOVX sequences of the invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction fragment length polymorphisms (RFLPs).
Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If predicted coding sequences, such as those in SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, are used, a more appropriate number of primers for positive individual identification would be S00-2,000.
Predictive Medicine The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the invention relates to diagnostic assays for determining NOVX
protein and/or nucleic acid expression as well as NOVX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with aberrant NOVX
expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. For example, mutations in A NOVX gene can be assayed in a biological sample. Such assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with NOVX protein, nucleic acid expression, or biological activity.
Another aspect of the invention provides methods for determining NOVX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as "pharmacogenomics") Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to a particular agent.) Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX in clinical trials.
These and other agents are described in further detail in the following sections.
DIAGNOSTIC ASSAYS
An exemplary method for detecting the presence or absence of NOVX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes NOVX protein such that the presence of NOVX is detected in the biological sample. An agent for detecting NOVX mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to NOVX mRNA or genomic DNA.
The nucleic acid probe can be, for example, a full-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 86, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to NOVX mRNA
or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.
An agent for detecting NOVX protein is an antibody capable of binding to NOVX
protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab')2) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect NOVX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo.
For example, in vitro techniques for detection of NOVX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of NOVX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of NOVX genomic DNA
include Southern hybridizations. Furthermore, in vivo techniques for detection of NOVX
protein include introducing into a subject a labeled anti-NOVX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.
In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.
In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting NOVX protein, mRNA, or genomic DNA, such that the presence of NOVX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of NOVX protein, mRNA or genomic DNA in the control sample with the presence of NOVX protein, mRNA or genomic DNA in the test sample.
The invention also encompasses kits for detecting the presence of NOVX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting NOVX protein or mRNA in a biological sample; means for determining the amount of NOVX in the sample; and means for comparing the amount of NOVX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect NOVX protein or nucleic acid.
PROGNOSTIC ASSAYS
The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant NOVX
expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity.
Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant NOVX expression or activity in which a test sample is obtained from a subject and NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant NOVX
expression or activity. As used herein, a "test sample" refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue.
Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant NOVX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder.
Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant NOVX expression or activity in which a test sample is obtained and NOVX protein or nucleic acid is detected (e.g., wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant NOVX
expression or activity).
The methods of the invention can also be used to detect genetic lesions in A
NOVX
gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding A NOVX-protein, or the misexpression of the NOVX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least one of: (i) a deletion of one or more nucleotides from A NOVX gene; (ii) an addition of one or more nucleotides to A
NOVX gene; (iii) a substitution of one or more nucleotides of A NOVX gene, (iv) a chromosomal rearrangement of A NOVX gene; (v) an alteration in the level of a messenger RNA transcript of A NOVX gene, (vi) aberrant modification of A NOVX gene, such as of the methylation pattern of the genomic DNA, (vii) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of A NOVX gene, (viii) a non-wild-type level of A NOVX
protein, (ix) allelic loss of A NOVX gene, and (x) inappropriate post-translational modification of A NOVX protein. As described herein, there are a large number of assay techniques known in the art which can be used for detecting lesions in A NOVX gene. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.
However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.
In certain embodiments, detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Patent Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et al., 1988. Science 241: 1077-1080; and Nakazawa, et al., 1994.
Proc. Natl.
Acad. Sci. USA 91: 360-364), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (see, Abravaya, et al., 1995. Nucl. Acids Res. 23:
675-682).
This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to A
NOVX gene under conditions such that hybridization and amplification of the NOVX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.
Alternative amplification methods include: self sustained sequence replication (see, Guatelli, et al., 1990. Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177);
Q(3 Replicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.
In an alternative embodiment, mutations in A NOVX gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared.
Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Patent No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.
In other embodiments, genetic mutations in NOVX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density arrays containing hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al., 1996. Human Mutation 7: 244-255; Kozal, et al., 1996. Nat. Med. 2: 753-759. For example, genetic mutations in NOVX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et al., supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes.
This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected.
Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.
In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the NOVX gene and detect mutations by comparing the sequence of the sample NOVX with the corresponding wild-type (control) sequence.
Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl.
Acad. Sci. USA
74: 5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al., 1995.
Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g., PCT
International Publication No. WO 94/16101; Cohen, et al., 1996. Adv.
Chromatography 36:
127-162; and Griffin, et al., 1993. Appl. Biochem. Biotechnol. 38: 147-159).
Other methods for detecting mutations in the NOVX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA
or RNA/DNA heteroduplexes. See, e.g., Myers, et al., 1985. Science 230: 1242. In general, the art technique of "mismatch cleavage" starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type NOVX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, 1 S RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with S i nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton, et al., 1988. Proc. Natl.
Acad. Sci. USA 85:
4397; Saleeba, et al., 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection.
In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA
mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in NOVX cDNAs obtained from samples of cells. For example, the mutt enzyme of E.
coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T
at G/T mismatches. See, e.g., Hsu, et al., 1994. Carcinogenesis 15: 1657-1662.
According to an exemplary embodiment, a probe based on A NOVX sequence, e.g., a wild-type NOVX
sequence, is hybridized to a cDNA or other DNA product from a test cell(s).
The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Patent No. 5,459,039.
In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in NOVX genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, et al., 1989. Proc. Natl. Acad. Sci. USA: 86:
2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl. 9: 73-79.
Single-stranded DNA fragments of sample and control NOVX nucleic acids will be denatured S and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility. See, e.g., Keen, et al., 1991.
Trends Genet. 7: S.
In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE). See, e.g., Myers, et al., 1985. Nature 313: 495.
When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 by of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753.
Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al., 1986. Nature 324: 163;
Saiki, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.
Alternatively, allele specific amplification technology that depends on selective PCR
amplification may be used in conjunction with the instant invention.
Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al., 1989. Nucl. Acids Res. 17: 2437-2448) or at the extreme 3'-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11: 238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. See, e.g., Gasparini, et al., 1992. Mol. Cell Probes 6: 1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3'-terminus of the 5' sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.
The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving A NOVX
gene.
Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which NOVX is expressed may be utilized in the prognostic assays described herein.
However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.
PHARMACOGENOMICS
Agents, or modulators that have a stimulatory or inhibitory effect on NOVX
activity (e.g., NOVX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders (The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.) In conjunction with such treatment, the pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of NOVX
protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agents) for therapeutic or prophylactic treatment of the individual.
Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol., 23: 983-985; Linder, 1997. Clin.
Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.
As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT
2) and cytochrome Pregnancy Zone Protein Precursor enzymes CYP2D6 and CYP2C 19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C 19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.
Thus, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agents) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with A NOVX modulator, such as a modulator identified by one of the exemplary screening assays described herein.
MONITORING OF EFFECTS DURING CLINICAL TRIALS
Monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase NOVX gene expression, protein levels, or upregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting decreased NOVX gene expression, protein levels, or downregulated NOVX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease NOVX gene expression, protein levels, or downregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting increased NOVX gene expression, protein levels, or upregulated NOVX activity.
In such clinical trials, the expression or activity of NOVX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a "read out" or markers of the immune responsiveness of a particular cell.
By way of example, and not of limitation, genes, including NOVX, that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates NOVX activity (e.g., identified in a screening assay as described herein) can be identified.
Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of NOVX and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of NOVX or other genes. In this manner, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent.

In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of A NOVX protein, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the NOVX
protein, mRNA, or genomic DNA in the pre-administration sample with the NOVX
protein, mRNA, or genomic DNA in the post administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of NOVX
to higher levels than detected, i.e., to increase the effectiveness of the agent.
Alternatively, decreased administration of the agent may be desirable to decrease expression or activity of NOVX to lower levels than detected, i.e., to decrease the effectiveness of the agent.
Methods of Treatment The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant NOVX expression or activity. The disorders include cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease, AIDS, bronchial asthma, Crohn's disease; multiple sclerosis, treatment of Albright Hereditary Ostoeodystrophy, and other diseases, disorders and conditions of the like.
These methods of treatment will be discussed more fully, below.
DISEASE AND DISORDERS
Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner.
Therapeutics that may be utilized include, but are not limited to: (i) an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (ii) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are "dysfunctional" (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to "knockout" endogenous function of an aforementioned peptide by homologous recombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or (v) modulators ( i.e., inhibitors, agonists and antagonists, including additional peptide mimetic of the invention or antibodies specific to a peptide of the invention) that alter the interaction between an aforementioned peptide and its binding partner.
Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability.
Increased or decreased levels can be readily detected by quantifying peptide and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity of the expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, in situ hybridization, and the like).
PROPHYLACTIC METHODS
In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant NOVX expression or activity, by administering to the subject an agent that modulates NOVX expression or at least one NOVX activity.
Subjects at risk for a disease that is caused or contributed to by aberrant NOVX
expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the NOVX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of NOVX
aberrancy, for example, A NOVX agonist or NOVX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections.
Therapeutic Methods Another aspect of the invention pertains to methods of modulating NOVX
expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of NOVX protein activity associated with the cell. An agent that modulates NOVX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of A NOVX protein, a peptide, A NOVX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more NOVX protein activity.
Examples of such stimulatory agents include active NOVX protein and a nucleic acid molecule encoding NOVX
that has been introduced into the cell. In another embodiment, the agent inhibits one or more NOVX protein activity. Examples of such inhibitory agents include antisense NOVX nucleic acid molecules and anti-NOVX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of A
NOVX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) NOVX expression or activity. In another embodiment, the method involves administering A NOVX
protein or nucleic acid molecule as therapy to compensate for reduced or aberrant NOVX
expression or activity.
Stimulation of NOVX activity is desirable in situations in which NOVX is abnormally downregulated and/or in which increased NOVX activity is likely to have a beneficial effect.
One example of such a situation is where a subject has a disorder characterized by aberrant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia).

Determination of the Biological Effect of the Therapeutic In various embodiments of the invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue.
In various specific embodiments, in vitro assays may be performed with representative cells of the types) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model system known in the art may be used prior to administration to human subjects.
Prophylactic and Therapeutic Uses of the Compositions of the Invention The NOVX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders including, but not limited to: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.
As an example, a cDNA encoding the NOVX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof.
By way of non-limiting example, the compositions of the invention will have efficacy for treatment of patients suffering from: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias.
Both the novel nucleic acid encoding the NOVX protein, and the NOVX protein of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. A
further use could be as an anti-bacterial molecule (i.e., some peptides have been found to possess anti-bacterial properties). These materials are further useful in the generation of antibodies, which immunospecifically-bind to the novel substances of the invention for use in therapeutic or diagnostic methods.
The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.
S
Examples EXAMPLE 1.
The NOV 1 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 1A.
Table 1A. NOVl Sequence Analysis SEQ ID NO: 1 813 by NOVla, CAAAACAAATTAAAAGATGAAGGAATACTATATCCATGTAACATGTGCCAATTTAACG

CGS8S48-O1 '~CGGTGGAAAGTCAGAACTTCTGAAATCAGGAAGCAGCAAATCCACACTAAAGCACA

DNA

TATGGACAGAAAGCAGCAAAGACTTGTCTATCAGCCGACTCCTGTCACAGACTTTTCG
Sequence TGGCAAAGAGAATGATACAGATTTGGACCTGAGATATGACACCCCAGAACCTTATTCT

GAGCAAGACCTCTGGGACTGGCTGAGGAACTCCACAGACCTTCAAGAGCCTCGGCCCA

GGGCCAAGAGAAGGCCCATTGTTAAAACGGGCAAGTTTAAGAAAATGTTTGGATGGGG

CGATTTTCATTCCAACATCAAAACAGTGAAGCTGAACCTGTTGATAACTGGGAAAATT

GTAGATCATGGCAATGGGACATTTAGTGTTTATTTCAGGCATAATTCAACTGGTCAAG

GGAATGTATCTGTCAGCTTGGTACCCCCTACAAAAATCGTGGAATTTGACTTGGCACA

ACAAACCGTGATTGATGCCAAAGATTCCAAGTCTTTTAATTGTCGCATTGAATATGAA

AAGGTTGACAAGGCTACCAAGAACACACTCTGCAACTATGACCCTTCAAAAACCTGTT

ACCAGGAGCAAACCCAAAGTCATGTATCCTGGCTCTGCTCCAAGCCCTTTAAGGTGAT

CTGTATTTACATTTCCTTTTATAGTACAGATTATAAACTGGTACAGAAAGTGTGCCCT

GACTACAACTACCACAGTGACACACCTTACTTTCCCTCGGGATGAAGGTGAACATGGG

G

OItF Start: ATG O1RF
at 17 Stop:
TGA
at 797 SEQ ID NO: 2 260 as MW at 29905.SkD

NOVla, MKEYYIHVTCANLTNGGKSELLKSGSSKSTLKHIWTESSKDLSISRLLSQTFRGKEND

CGSHS4H-Ol TDLDLRYDTPEPYSEQDLWDWLRNSTDLQEPRPRAKRRPIVKTGKFKKMFGWGDFHSN

PrOteln Se ueriCe IKTVKLNLLITGKIVDHGNGTFSVYFRHNSTGQGNVSVSLVPPTKIVEFDLAQQTVID

q AKDSKSFNCRIEYEKVDKATKNTLCNYDPSKTCYQEQTQSHVSWLCSKPFKVICIYIS

FYSTDYKLVQKVCPDYNYHSDTPYFPSG

SEQ ID NO: 3 771 by NOVIb, GGATCCGTAACATGTGCCAATTTAACGAACGGTGGAAAGTCAGAACTTCTGAAATCAG

174307940 DNA G~GCAGCAAATCCACACTAAAGCACATATGGACAGAAAGCAGCAAAGACTTGTCTAT

CAGCCGACTCCTGTCACAGACTTTTCGTGGCAAAGAGAATGATACAGATTTGGACCTG
SequeriCe AGATATGACACCCCAGAACCTTATTCTGAGCAAGACCTCTGGGACTGGCTGAGGAACT

CCACAGACCTTCAAGAGCCTCGGCCCAGGGCCAAGAGAAGGCCCATTGTTAAAACGGG

CAAGTTTAAGAAAATGTTTGGATGGGGCGATTTTCATTCCAACATCAAAACAGTGAAG

CTGAACCTGTTGATAACTGGGAAAATTGTAGATCATGGCAATGGGACATTTAGTGTTT

ATTTCAGGCATAATTCAACTGGTCAAGGGAATGTATCTGTCAGCTTGGTACCCCCTAC

AAAAATCGTGGAATTTGACTTGGCACAACAAACCGTGATTGATGCCAAAGATTCCAAG

TCTTTTAATTGTCGCATTGAATATGAAAAGGTTGACAAGGCTACCAAGAACACACTCT

GCAACTATGACCCTTCAAAAACCTGTTACCAGGAGCAAACCCAAAGTCATGTATCCTG

GCTCTGCTCCAAGCCCTTTAAGGTGATCTGTATTTACATTTCCTTTTATAGTACAGAT

TATAAACTGGTACAGAAAGTGTGCCCTGACTACAACTACCACAGTGACACACCTTACT

TTCCCTCGGGACTCGAG

ORF Start: GGA~ at ~ 1 . ORF
Stop: E at 772 SEQ ID NO: 4 2S7 as MW at 29326.8kD

NOVlb, GSVTCANLTNGGKSELLKSGSSKSTLKHIWTESSKDLSISRLLSQTFRGKENDTDLDL

1743O794O PrOteln RYDTPEPYSEQDLWDWLRNSTDLQEPRPRAKRRPIVKTGKFKKMFGWGDFHSNIKTVK

SeqlleriCe LNLLITGKIVDHGNGTFSVYFRHNSTGQGNVSVSLVPPTKIVEFDLAQQTVIDAKDSK

SFNCRIEYEKVDKATKNTLCNYDPSKTCYQEQTQSHVSWLCSKPFKVICIYISFYSTD

YKLVQKVCPDYNYHSDTPYFPSGLE

SEQ ID NO: S 813 by NOV1C, CAAAACAAATTAAAAGATGAAGGAATACTATATCCATGTAACATGTGCCAATTTAACG

CGS8S48-02 DNA ~'CGGTGGAAAGTCAGAACTTCTGAAATCAGGAAGCAGCAAATCCACACTAAAGCACA

TATGGACAGAAAGCAGCAAAGACTTGTCTATCAGCCGACTCCTGTCACAGACTTTTCG
SeqllenCe TGGCAAAGAGAATGATACAGATTTGGACCTGAGATATGACACCCCAGAACCTTATTCT

GAGCAAGACCTCTGGGACTGGCTGAGGAACTCCACAGACCTTCAAGAGCCTCGGCCCA

GGGCCAAGAGAAGGCCCATTGTTAAAACGGGCAAGTTTAAGAAAATGTTTGGATGGGG

CGATTTTCATTCCAACATCAAAACAGTGAAGCTGAACCTGTTGATAACTGGGAAAATT

GTAGATCATGGCAATGGGACATTTAGTGTTTATTTCAGGCATAATTCAACTGGTCAAG

GGAATGTATCTGTCAGCTTGGTACCCCCTACAAAAATCGTGGAATTTGACTTGGCACA

ACAAACCGTGATTGATGCCAAAGATTCCAAGTCTTTTAATTGTCGCATTGAATATGAA

AAGGTTGACAAGGCTACCAAGAACACACTCTGCAACTATGACCCTTCAAAAACCTGTT

ACCAGGAGCAAACCCAAAGTCATGTATCCTGGCTCTGCTCCAAGCCCTTTAAGGTGAT

CTGTATTTACATTTCCTTTTATAGTACAGATTATAAACTGGTACAGAAAGTGTGCCCT

GACTACAACTACCACAGTGACACACCTTACTTTCCCTCGGGATGAAGGTGAACATGGG

G

ORF Start: ATG at 17 ORF Stop:
TGA at 797 SEQ ID NO: 6 260 as MW at 2990S.SkD

NOV1C, MKEYYIHVTCANLTNGGKSELLKSGSSKSTLKHIWTESSKDLSISRLLSQTFRGKEND

CGS8S48-O2 PrOtelri TDLDLRYDTPEPYSEQDLWDWLRNSTDLQEPRPRAKRRPIVKTGKFKKMFGWGDFHSN

Se uenCe IKTVKLNLLITGKIVDHGNGTFSVYFRHNSTGQGNVSVSLVPPTKIVEFDLAQQTVID
q AKDSKSFNCRIEYEKVDKATKNTLCNYDPSKTCYQEQTQSHVSWLCSKPFKVICIYIS

FYSTDYKLVQKVCPDYNYHSDTPYFPSG

SEQ ID NO: 7 627 by NOVld, CAAAACAAATTAAAAGATGAAGGAATACTATATCCATGTAACATGTGCCAATTTAACG

CGS8S48-03 DNA '~CGGTGGAAAGTCAGAACTTCTGAAATCAGGAAGCAGCAAATCCACACTAAAGCACA

TATGGACAGAAAGCAGCAAAGACTTGTCTATCAGCCGACTCCTGTCACAGACTTTTCG

SequeriCe TGGCAAAGAGAATGATACAGATTTGAACCTGTTGATAACTGGGAAAATTGTAGATCAT

GGCAATGGGACATTTAGTGTTTATTTCAGGCATAATTCAACTGGTCAAGGGAATGTAT

CTGTCAGCTTGGTACCCCCTACAAAAATCGTGGAATTTGACTTGGCACAACAAACCGT

GATTGATGCCAAAGATTCCAAGTCTTTTAATTGTCGCATTGAATATGAAAAGGTTGAC

AAGGCTACCAAGAACACACTCTGCAACTATGACCCTTCAAAAACCTGTTACCAGGAGC

AAACCCAAAGTCATGTATCCTGGCTCTGCTCCAAGCCCCTTAAGGTGATCTGTATTTA

CATTTCCTTTTATAGTACAGATTATAAACTGGTACAGAAAGTGTGCCCTGACTACAAC

TACCACAGTGACACACCTTACTTTCCCTCGGGATGAAGGTGAACATG

ORF Start: ATG at 17 ORF Stop:
TGA
at 614 SEQ ID NO: 8 199 as MW at 22496.1kD

NOVld, MKEYYIHVTCANLTNGGKSELLKSGSSKSTLKHIWTESSKDLSISRLLSQTFRGKEND

CGSHS4H-O3 PTOtelri TDLNLLITGKIVDHGNGTFSVYFRHNSTGQGNVSVSLVPPTKIVEFDLAQQTVIDAKD

SKSFNCRIEYEKVDKATKNTLCNYDPSKTCYQEQTQSHVSWLCSKPLKVICIYISFYS

Se ueriCe q TDYKLVQKVCPDYNYHSDTPYFPSG

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 1B.

Table 1B.
Comparison of NOVla against NOVlb through NOVld.

NOVla Residues/Identities/

Protein SequenceMatch ResiduesSimilarities for the Matched Region NOVIb 8..260 236/253 (93%) 3..255 236/253 (93%) NOVIc 1..260 243/260 (93%) 1..260 243/260 (93%) NOV 1 d 1..260 161 /260 (61 %) 1..199 164/260 (62%) Further analysis of the NOVIa protein yielded the following properties shown in Table 1C.
Table 1C. Protein Sequence Properties NOVla PSort 0.5297 probability located in microbody (peroxisome); 0.3000 probability analysis: located in nucleus; 0.1000 probability located in mitochondrial matrix space;
0.1000 probability located in lysosome (lumen) SignalP No Known Signal Sequence Predicted analysis:
A search of the NOVIa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 1 D.
Table 1D. Geneseq Results for NOVla NOVla Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value ResiduesRegion ABB11858 Human neurexophilin homologue,8..260 253/253 (100%)e-152 SEQ ID N0:2228 - Homo Sapiens,53..305 253/253 (100%) 305 aa. [W0200157188-A2, AUG-2001 ]

AAB43066 Human ORFX ORF2830 polypeptide8..260 253/253 (100%)e-152 sequence SEQ ID N0:5660 1..253 253/253 (100%) - Homo Sapiens, 253 aa. [W0200058473-A2, OS-OCT-2000]

AAM57924 Human brain expressed single14..248 235/235 (100%)e-140 exon probe encoded protein SEQ 1..235 235/235 (100%) ID NO:

30029 - Homo Sapiens, 235 aa.

[W0200157275-A2, 09-AUG-2001]

AAB28778 Se-73 fragment encoded by gene 1..128 128/128 (100%) 45 - Homo sapiens, 128 aa. [W0200055198-A1, 21-SEP-2000]

AAB28779 Protein fragment encoded 104..231127/128 (99%)4e-72 by gene 45 - Homo Sapiens, 128 aa. 1..128 127/128 (99%) [W0200055198-A1, 21-SEP-2000]

In a BLAST search of public sequence databases, the NOV 1 a protein was found to have homology to the proteins shown in the BLASTP data in Table 1 E.
Table 1E. Public BLASTP
Results for NOVla Protein NOVla Identities/

Residues/ Expect AccessionProtein/Organism/Length Similarities for the Match Value Number Matched Portion Residues P58417 Neurexophilin 1 precursor8..260 253/253 (100%)e-151 - Homo Sapiens (Human), 271 19..271 253/253 (100%) aa.

Q61200 Neurexophilin 1 precursor8..260 253/253 (100%)e-151 - Mus musculus (Mouse), 253 1..253 253/253 (100%) as (fragment).

Q63366 Neurexophilin 1 precursor8..260 251/253 (99%) e-150 (Neurophilin) - Rattus 19..271 252/253 (99%) norvegicus (Rat), 271 aa.

095156 Neurexophilin 2 precursor72..260 153/189 (80%) 3e-93 - Homo sapiens (Human), 262 74..262 170/189 (88%) as (fragment).

Q28145 Neurexophilin 2 precursor72..260 153/189 (80%) 4e-93 (Neurophilin) - Bos 76..264 170/189 (88%) taurus (Bovine), 264 aa.

PFam analysis tein the domains the predicts containsshown in that the NOV
1 a pro Table 1 F.
Table 1F. Domain Analysis of NOVla Identities/
Pfam Domain NOVIa Match Region Similarities Expect Value for the Matched Region No Significant Matches Found _._...._..__...
EXAMPLE 2.
The NOV2 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 2A.

Table 2A. NOV2 Sequence Analysis ~~~~ SEQ~~ID NO: 9 ~~ 796 by NOV2a, AGGAGGAAGATGCAACTGACTCGCTGCTGCTTCGTGTTCCTGGTGCAGGGTAGCCTCT

DNA

TGACCACGAGGGCCAGCCCCGGCCCCGGGTGCCTCGGAAGCGGGGCCACATCTCACCT
SeClLleriCB

AAGTCCCGCCCCATGGCCAATTCCACTCTCCTAGGGCTGCTGGCCCCGCCTGGGGAGG

CTTGGGGCATTCTTGGGCAGCCCCCCAACCGCCCGAACCACAGCCCCCCACCCTCAGC

CAAGGTGAAGAAAATCTTTGGCTGGGGCGACTTCTACTCCAACATCAAGACGGTGGCC

CTGAACCTGCTCGTCACAGGGAAGATTGTGGACCATGGCAATGGGACCTTCAGCGTCC

ACTTCCAACACAATGCCACAGGCCAGGGAAACATCTC.CATCAGCCTCGTGCCCCCCAG

TAAAGCTGTAGAGTTCCACCAGGAACAGCAGATCTTCATCGAAGCCAAGGCCTCCAAA

ATCTTCAACTGCCGGATGGAGTGGGAGAAGGTAGAACGGGGCCGCCGGACCTCGCTTT

GCACCCACGACCCAGCCAAGATCTGCTCCCGAGACCACGCTCAGAGCTCAGCCACCTG

GAGCTGCTCCCAGCCCTTCAAAGTCGTCTGTGTCTACATCGCCTTCTACAGCACGGAC

TATCGGCTGGTCCAGAAGGTGTGCCCAGATTACAACTACCATAGTGATACCCCCTACT

ACCCATCTGGGTGACCCGGGGCAGGCCACAGAGGCCAGGCCA

OItF Start: ATG ORF Stop:
at 10 TGA
at 766 SEQ ID NO: 10 2S2 as MW at 28126.7kD

NOV2a, MQLTRCCFVFLVQGSLYLVICGQDDGPPGSEDPERDDHEGQPRPRVPRKRGHISPKSR

CGS8S42-O1 P~STLLGLLAPPGEAWGILGQPPNRPNHSPPPSAKVKKIFGWGDFYSNIKTVALNL
PrOt8lri SeCllleriCB LVTGKIVDHGNGTFSVHFQHNATGQGNISISLVPPSKAVEFHQEQQIFIEAKASKIFN

CRMEWEKVERGRRTSLCTHDPAKICSRDHAQSSATWSCSQPFKWCVYIAFYSTDYRL

VQKVCPDYNYHSDTPYYPSG

SEQ ID NO: 11 702 by NOV2b, GGATCCCAGGATGATGGTCCTCCCGGCTCAGAGGACCCTGAGCGTGATGACCACGAGG

CATGGCCAATTCCACTCTCCTAGGGCTGCTGGCCCCGCCTGGGGAGGCTTGGGGCATT
SeCIUeriC2 CTTGGGCAGCCCCCCAACCGCCCGAACCACAGCCCCCCACCCTCAGCCAAGGTGAAGA

AAATCTTTGGCTGGGGCGACTTCTACTCCAACATCAAGACGGTGGCCCTGAACCTGCT

CGTCACAGGGAAGATTGTGGACCATGGCAATGGGACCTTCAGCGTCCACTTCCAACAC

AATGCCACAGGCCAGGGAAACATCTCCATCAGCCTCGTGCCCCCCAGTAAAGCTGTAG

AGTTCCACCAGGAACAGCAGATCTTCATCGAAGCCAAGGCCTCCAAAATCTTCAACTG

CCGGATGGAGTGGGAGAAGGTAGAACGGGGCCGCCGGACCTCGCTCTGCACCCACGAC

CCAGCCAAGATCTGCTCCCGAGACCACGCTCAGAGCTCAGCCACCTGGAGCTGCTCCC

AGCCCTTCAAAGTCGTCTGTGTCTACATCGCCTTCTACAGCACGGACTATCGGCTGGT

CCAGAAGGTGTGCCCAGATTACAACTACCATAGTGATACCCCCTACTACCCATCTGGG

CTCGAG

ORF Start: GGA ORF Stop:
at 1 S at SEQ ID NO: 12 234 as MW at 26037.OkD

NOV2b, GSQDDGPPGSEDPERDDHEGQPRPRVPRKRGHISPKSRPMANSTLLGLLAPPGEAWGI

169679583 PrOtelriLGQPPNRPNHSPPPSAKVKKIFGWGDFYSNIKTVALNLLVTGKIVDHGNGTFSVHFQH

Se Ll2riCe NATGQGNISISLVPPSKAVEFHQEQQIFIEAKASKIFNCRMEWEKVERGRRTSLCTHD

SG

PAKICSRDHAQSSATWSCSQPFKWCVYIAFYSTDYRLVQKVCPDYNYHSDTPYYP

LE

SEQ ID NO: 13 702 by NOV2C, GGATCCCAGGATGATGGTCCTCCCGGCTCAGAGGACCCTGAGCGTGATGACCACGAGG

CATGGCCAATTCCACTCTCCTAGGGCTGCTGGCCCCGCCTGGGGAGGCTTGGGGCATT
SCC]LleriCe CTTGGGCAGCCCCCCAACCGCCCGAACCACAGCCCCCCACCCTCAGCCAAGGTGAAGA
AAATCTTTGGCTGGGGCGACTTCTACTCCAACATCAAGACGGTGGCCCTGAACCTGCT
CGTCACAGGGAAGATTGTGGACCATGGCAATGGGACCTTCAGCGTCCACTTCCAACAC
AATGCCACAGGCCAGGGAAACATCTCCATCAGCCTCGTGCCCCCCAGTAAAGCTGTAG
AGTTCCACCAGGAACAGCAGATCTTCATCGAAGCCAAGGCCTCCAAAATCTTCAACTG
CCGGATGGAGTGGGAGAAGGTAGAACGGGGCCGCCGGACCTCGCTTTGCACCCACGAC

CCAGCCAAGATCTGCTCCCGAGACCACGCTCAGAGCTCAGCCACCTGGAGCTGCTCCC
AGCCCTTCAAAGTCGTCTGTGTCTACATCGCCTTCTACAGCACGGACTATCGGCTGGT
CCAGAAGGTGTGCCCAGATTACAACTACCATAGTGATACCCCCTACTACCCATCTGGG
CTCGAG
ORF Start: GGA at 1 ORF Stop: 5 at 703 SEQ ID NO: 14 234 as MW at 26037.OkD
NOV2C, GSQDDGPPGSEDPERDDHEGQPRPRVPRKRGHISPKSRPMANSTLLGLLAPPGEAWGI
169679634 PrOteln L'GQPPNRPNHSPPPSAKVKKIFGWGDFYSNIKTVALNLLVTGKIVDHGNGTFSVHFQH
Se hence NATGQGNISISLVPPSKAVEFHQEQQIFIEAKASKIFNCRMEWEKVERGRRTSLCTHD
q PAKICSRDHAQSSATWSCSQPFKVVCVYIAFYSTDYRLVQKVCPDYNYHSDTPYYPSG
LE
Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 2B.
Table 2B. Comparison of NOV2a against NOV2b through NOV2c.
Protein Sequence NOV2a Residues/ Identities/
Match Residues Similarities for the Matched Region NOV2b 23..252 218/230 (94%) 3..232 218/230 (94%) NOV2c 23..252 218/230 (94%) 3..232 218/230 (94%) Further analysis of the NOV2a protein yielded the following properties shown in Table 2C.
Table 2C. Protein Sequence Properties NOV2a PSort 0.7666 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1000 probability located in endoplasmic reticulum (membrane);
0.1000 probability located in endoplasmic reticulum (lumen) SignalP Likely cleavage site between residues 23 and 24 analysis:
A search of the NOV2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 2D.
Table 2D. Geneseq Results for NOV2a NOV2a Identities/

Geneseq Protein/Organism/Length Residues/Similarities for [Patent Expect Identifier#, Date] Match the Matched Value ResiduesRegion AAU29174 Human PRO polypeptide 1..252 252/252 (100%) sequence e-154 #151 - Homo Sapiens, 252 1..252 252/252 (100%) aa.

[W0200168848-A2, 20-SEP-2001]

AAM39340 Human polypeptide SEQ 1..252 252/252 (100%)e-154 - Homo Sapiens, 252 aa. 1..252 252/252 (100%) [W0200153312-A1, 26-JC1L-2001]

AAB87571 Human PR01327 - Homo Sapiens,1..252 252/252 (100%)e-154 252 aa. [W0200116318-A2, 1..252 252/252 (100%) MAR-2001 ]

AAB66150 Protein of the invention 1..252 252/252 (100%)e-154 #62 -Unidentified, 252 aa. 1..252 252/252 (100%) [W0200078961-A1, 28-DEC-2000]

AAY99401 Human PR01327 (LTNQ687) 1..252 252/252 (100%)e-154 amino acid sequence SEQ ID N0:2181..252 252/252 (100%) -Homo Sapiens, 252 aa.

[W0200012708-A2, 09-MAR-2000]

In a BLAST search of public sequence databases, the NOV2a protein was found to have homology to the proteins shown in the BLASTP data in Table 2E.
Table 2E. Public BLASTP Results for NOV2a Protein NOV2a Identities/

Residues/ Expect AccessionProtein/Organism/Length Similarities for the Match Value Number Matched Portion Residues Q91 VXS SIMILAR TO NEUREXOPHIL11V1..252 243/252 (96%) e-148 3 - Mus musculus (Mouse),1..252 246/252 (97%) 252 aa.

Q9Z2N5 Neurexophilin 3 precursor1..252 242/252 (96%) e-148 - Rattus norvegicus (Rat), 252 1..252 246/252 (97%) aa.

095157 Neurexophilin 3 - Homo 32..252 221/221 (100%)e-134 Sapiens (Human), 221 as (fragment).1..221 221/221 (100%) P58417 Neurexophilin 1 precursor79..252 114/175 (65%) 7e-68 - Homo Sapiens (Human), 271 97..271 143/175 (81%) aa.

Q63366 Neurexophilin 1 precursor79..252 114/175 (65%) 7e-68 (Neurophilin) - Rattus 97..271 143/175 (81%) norvegicus (Rat), 271 aa.

PFam analysis predicts that the domains the the NOV2a protein contains shown in Table 2F.
Table 2F. Domain Analysis of NOV2a Identities/
Pfam Domain NOV2a Match Region Similarities Expect Value for the Matched Region No Significant Matches Found EXAMPLE 3.
The NOV3 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 3A.
Table 3A. NOV3 Sequence Analysis SEQ ID NO: 1 S 1173 by NOV3a, GCCCTGCATCATGGAAACTCTTTCTAATGCAAGTGGTACTTTTGCCATACGCCTTTTA

CGS8S4O-O1 ~GATACTGTGTCAAGATAACCCTTCGCACAACGTGTTCTGTTCTCCTGTGAGCATCT

DNA

CCTCTGCCCTGGCCATGGTTCTCCTAGGGGCAAAGGGAAACACCGCAACCCAGATGGC

SequeriCe CCAGATAGAGTCTCTGCTCTGTCACCCAGGCTGGAGTGCAGACATTCATCGGGCTTTC

CAGTCGCTTCTCACTGAAGTGAACAAGGCTGGCACACAGTACCTGCTGAGAACGGCCA

ACAGGCTCTTTGGAGAGAAAACTTGTCAGTTCCTCTCAACGTTTAAGGAATCCTGTCT

TCAATTCTACCATGCTGAGCTGAAGGAGCTTTCCTTTATCAGAGCTGCAGAAGAGTCC

AGGAAACACATCAACACCTGGGTCTCAAAAAAGACCGAAGGTAAAATTGAAGAGTTGT

TGCCGGGTAGCTCAATTGATGCAGAAACCAGGCTGGTTCTTGTGAATGCTGTCTATTT

CAGAGGAAACTGGGATGAACAGTTTGACAAGGAGAACACCGAGGAGAGACTGTTTAAA

GTCAGCAAGGCGAGTAAGGAGGAGAAACCTGTGCAAATGATGTTTAAGCAATCTACTT

TTAAGAAGACCTATATAGGAGAAATATTTACCCAAATCTTGGTGCTTCCATATGTTGG

CAAGGAACTGAATATGATCATCATGCTTCCGGACGAGACCACTGACTTGAGAACGGTG

GAAAAAAGTCTCACTTTTGAGAAACTCACAGCCTGGACCAAGCCAGACTGTATGAAGA

GTACTGAGGTTGAAGTTCTCCTTCCAAAATTTAAACTACAAGAGGATTATGACATGGA

ATCTGTGCTTCGGCATTTGGGAATTGTTGATGCCTTCCAACAGGGCAAGGCTGACTTG

TCGGCAATGTCAGCGGAGAGAGACCTGTGTCTGTCCAAGTTCGTGCACAAGAGTTTTG

TGGAGGTGAATGAAGAAGGCACCGAGGCAGCGGCAGCGTCGAGCTGCTTTGTAGTTGC

AGAGTGCTGCATGGAATCTGGCCCCAGGTTCTGTGCTGACCACCCTTTCCTTTTCTTC

ATCAGGCACAACAGAGCCAACAGCATTCTGTTCTGTGGCAGGTTCTCATCGCCATAAA

GGGTGCACTTACC

ORF Start: ATG ORF Stop:
at 11 TAA
at 1157 SEQ ID NO: 16 382 as MW at 43163.1kD

NOV3a, METLSNASGTFAIRLLKILCQDNPSHNVFCSPVSISSALAMVLLGAKGNTATQMAQIE

PrOteln HAELKELSFIRAAEESRKHINTWVSKKTEGKIEELLPGSSIDAETRLVLVNAWFRGN

Se ueriCe WDEQFDKENTEERLFKVSKASKEEKPVQMMFKQSTFKKTYIGEIFTQILVLPYVGKEL

q NMIIMLPDETTDLRTVEKSLTFEKLTAWTKPDCMKSTEVEVLLPKFKLQEDYDMESVL

RHLGIVDAFQQGKADLSAMSAERDLCLSKFVHKSFVEVNEEGTEAAAASSCFWAECC

MESGPRFCADHPFLFFIRHNRANSILFCGRFSSP

Further analysis of the NOV3a protein yielded the following properties shown in Table 3B.
Table 3B. Protein Sequence Properties NOV3a PSort..~.~.~~ ~~~0.6881 probability located~l~in~I~mitochondrial inner membrane; 0.6500 probability analysis: located in plasma membrane; 0.3773 probability located in mitochondrial intermembrane space; 0.3157 probability located in mitochondrial matrix space SignalP No Known Signal Sequence Predicted analysis:
A search of the NOV3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 3C.

Table 3C. Geneseq Results for NOV3a NOV3a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value ResiduesRegion AAY55841Human cytoplasmic antiproteinase-31..382 328/382 (85%)0.0 protein (CAP-3) - Homo 1..376 353/382 (91%) Sapiens, 376 aa. [W09957273-A2, 11-NOV-1999]

AAR99254Cytoplasmic antiproteinase-31..382 328/382 (85%)0.0 protein -Homo Sapiens, 376 aa. [W09624650-1..376 353/382 (91%) A2, 15-AUG-1996]

AAU30834Novel human secreted protein1..382 324/382 (84%)0.0 #1325 -Homo Sapiens, 566 aa. 191..566351/382 (91%) [W0200179449-A2, 25-OCT-2001 ]

AAB11125Human thrombin inhibitor 1..382 279/382 (73%)e-153 protein -Homo sapiens, 376 aa. [LJS6133422-1..376 314/382 (82%) A, 17-OCT-2000]

AAB59176Thrombin inhibitor protein1..382 279/382 (73%)e-153 -Unidentified, 376 aa. [US6156540-A,1..376 314/382 (82%) 05-DEC-2000]

In a 3a protein BLAST was found search to of public sequence databases, the NOV

have homology to the proteins shown in the BLASTP data in Table 3D.
Table 3D. Public BLASTP Results for NOV3a NOV3a Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the MatchedValue Number ResiduesPortion P50453 Cytoplasmic antiproteinase 1..382 328/382 0.0 3 (CAP3) (85%) (CAP-3) (Protease inhibitor1..376 353/382 9) (Serpin (91%) B9) - Homo Sapiens (Human), 376 aa.

Q96J44 SERINE (OR CYSTEINE) 1..382 279/382 e-153 (73%) PROTEINASE INHIBITOR, CLADE1..376 314/382 B (82%) (OVALBUMIN), MEMBER 6 -Homo sapiens (Human), 376 aa.

P35237 Placental thrombin inhibitor1..382 278/382 e-152 (72%) (Cytoplasmic antiproteinase)1..376 312/382 (CAP) (80%) (Protease inhibitor 6) -Homo Sapiens (Human), 376 aa.

002739 Serine proteinase inhibitor1..382 252/382 e-139 B-43 - Bos (65%) taurus (Bovine), 378 aa. 1..378 303/382 (78%) e-136 (SER1NE (OR CYSTEINE) 1..378 301/383 (78%) PROTE1NASE INHIBITOR, CLADE
B

(OVALBUM1N), MEMBER 6) -Mus musculus (Mouse), 378 aa.

PFam analysis predicts that the NOV3a protein contains the domains shown in the Table 3E.
Table 3E. Domain Analysis of NOV3a Identities/
Pfam Domain NOV3a Match Region Similarities Expect Value for the Matched Region serpin: domain 1 of 1 1..382 170/400 (42%) 8.8e-1S9 314/400 (78%) EXAMPLE 4.
The NOV4 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 4A.
Table 4A. NOV4 Sequence Analysis SEQ ID NO: 17 S02 by NOV4a, GCAATATTGGCAACATCCCAATGGCCCTGTCCTTTTCTTTACTGATGGCCGTGCTGGT

DNA

GGTAATAGGAGGGCCTTGATACTCCTGGCACAAATGGGAAGAATCTCTCCTTTCTCCT

SeqlleriCe GCCTGAAGGACAGACATGACTTTGGATTCCCCCAGGAGGAGTTTGATGGCAACCAGTT

CCAGAAGGCTCAAGCCATCTCTGTCCTCCATGAGATGATCCAGCAGACCTTCAATCTC

TTCAGCACAAAGGACTCATCTGCTACTTGGGAACAGAGCCTCCTAGAAAAATTTTCCA

CTGAACTTAACCAGCAGCTGACAGAGAAGAAATACAGCCCTTGTGCCTGGGAGGTTGT

CAGAGCAGAAATCATGAGATCCTTCTCTTTATCAAAAATTTTTCAAGAAAGATTAAGG

AGGAAGGAATGAAACCTGTTTCAACATGGAAATGATCT

ORF Start: ATG ORF Stop:
at 21 TGA
at 474 SEQ ID NO: 18 1 S 1 MW at 17402.81cD
as NOV4a, MALSFSLLMAVLVLSYKSICSLGCDLPQTHSLGNRRALILLAQMGRISPFSCLKDRHD

PIOtelri TEKKYSPCAWEVVRAEIMRSFSLSKIFQERLRRKE
Sequence SEQ ID NO: 19 396 by NOV4b, GGATCCTGTGATCTGCCTCAGACCCACAGCCTGGGTAATAGGAGGGCCTTGATACTCC

ATTCCCCCAGGAGGAGTTTGATGGCAACCAGTTCCAGAAGGCTCAAGCCATCTCTGTC

SeqlleriCe CTCCATGAGATGATCCAGCAGACCTTCAATCTCTTCAGCACAAAGGACTCATCTGCTA

CTTGGGAACAGAGCCTCCTAGAAAAATTTTCCACTGAACTTAACCAGCAGCTGACAGA

GAAGAAATACAGCCCTTGTGCCTGGGAGGTTGTCAGAGCAGAAATCATGAGATCCTTC

TCTTTATCAAAAATTTTTCAAGAAAGATTAAGGAGGAAGGAACTCGAG

ORF Start: GGA ORF Stop:
at 1 at 397 SEQ ID NO: 20 132 as MW at 15360.31cD

NOV4b, GSCDLPQTHSLGNRRALILLAQMGRISPFSCLKDRHDFGFPQEEFDGNQFQKAQAISV

174308150 Protein~LHEMIQQTFNLFSTKDSSATWEQSLLEKFSTELNQQLTEKKYSPCAWEVVRAEIMRSF~

SLSKIFQERLRRKELE

Sequence Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 4B.
Table 4B. Comparison of NOV4a against NOV4b and NOV4c.
Protein Sequence NOV4a"Residues/ Identities/
Match Residues Similarities for the Matched Region NOV4b 24..151 128/128 (100%) 3..130 128/128 (100%) Further analysis of the NOV4a protein yielded the following properties shown in Table 4C.
Table 4C. Protein Sequence Properties NOV4a PSort 0.5231 probability located in outside; 0.1317 probability located in microbody analysis: (peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane);
0.1000 probability located in endoplasmic reticulum (lumen) SignalP Likely cleavage site between residues 24 and 25 analysis:
A search of the NOV4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 4D.
Table 4D. Geneseq Results for NOV4a NOV4a Identities/
Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region AAP20108 Sequence encoded by leukocyte 1..151 151/189 (79%) 7e-77 interferon LeIF F cDNA - Homo 1..189 151/189 (79%) Sapiens, 189 aa. [GB2079291-A, 20-JAN-1982]
AAP40123 Sequence encoded by the cDNA insert 1..151 150/189 (79%) 3e-76 of the recombinant plasmid CG-pBR 1..189 150/189 (79%) 322/HLycIFN-1'b - Homo sapiens, 189 aa. [EP100561-A, 15-FEB-1984]
AAP30179 Sequence of a polypeptide with human 1..151 150/189 (79%) 3e-76 lymphoblastoid interferon activity 1..189 150/189 (79%) encoded by plasmid CG-pBR 322/HL
gamma cIFN-1'b - Homo Sapiens, 189 aa. [EP76489-A, 13-APR-1983]

AAB49780Human interferon alpha-f 1..151 141/189 2e-71 ammo acid (74%) sequence - Homo Sapiens, 1..189 145/189 189 aa. (76%) [W0200107608-Al, O1-FEB-2001]

AAR62368Interferon alpha consensus 1..151 139/189 7e-69 sequence - (73%) Synthetic, 187 aa. [W09420122-A,1..187 144/189 15- (75%) SEP-1994]

In a BLAST search of public sequence databases, the NOV4a protein was found to have homology to the proteins shown in the BLASTP data in Table 4E.
Table 4E. Public BLASTP Results for NOV4a NOV4a Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched Value Number ResiduesPortion E968396 ARTIFICIAL SEQUENCE FOR 1..151 151/189 (79%)3e-76 CDNA INSERT OF 1..189 151/189 (79%) RECOMBINANT PLASMID CG-PBR 322/HLYCIFN-1'B - vectors, aa.

E968985 POLYPEPTIDE FOR THE USE 1..151 151/189 (79%)3e-76 OF

IMMUNOMODULATOR, ANTI- 1..189 151/189 (79%) TUMOR-AGENT - vectors, 189 aa.

P01568 Interferon alpha-21 precursor1..1 151/189 (79%)3e-76 (Interferon alpha-F) (LeIF1..189 151/189 (79%) F) - Homo Sapiens (Human), 189 aa.

CAA00629 ARTIFICIAL SEQUENCE FOR 1..151 150/189 (79%)1e-75 CDNA INSERT OF 1..189 150/189 (79%) RECOMBINANT PLASMID CG-PBR 322/HLYCIFN-1'B - synthetic construct, 189 aa.

Q14608 LEUKOCYTE INTERFERON- 9..151 143/181 (79%)3e-72 ALPHA - Homo sapiens (Human),1..181 143/181 (79%) 181 aa.

PFam analysis predicts that the NOV4a protein contains the domains shown in the Table 4F.
Table 4F. Domain Analysis of NOV4a Identities/

Pfam Domain NOV4a Match Region Similarities Expect Value for the Matched Region interferon: domain1..115 81/116 (70%) 4.9e-71 1 of 2 109/116 (94%) interferon: domain116..151 27/36 (7S%) 1e-19 2 of 2 33/36 (92%) EXAMPLE 5.
The NOVS clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table SA.
Table SA. NOVS Sequence Analysis SEQ ID NO: 21 203 by NOVSa, ACCTCTTTGCCACCATACCATGAAGGTATGCGTGATTGTCCTGTCTCTCCTCGTGATA
CGS8514-Ol DNA ATAGCCGCCTTCTGCTCTGTAGCACTCTCAGCACCGAATTCCAAACCAAAAGAGGCAA
GCAAGTCTGCGCTGACCCCAGTGAGTCCTGGGTCCAGGAGTACGTGTATGACCTGGAA
SequeriCe CTGAACTGAGCTGCTCAGAGACAGGAAGT
ORF Start: ATG at 20 ORF Stop: TGA at 176 SEQ ID NO: 22 S2 as MW at 5408.4kD
NOVSa, MKVCVIVLSLLVIIAAFCSVALSAPNSKPKEASKSALTPVSPGSRSTCMTWN
CGS8S14-O1 Protein Sequence Further analysis of the NOVSa protein yielded the following properties shown in Table SB.
Table SB. Protein Sequence Properties NOVSa PSort 0.8200 probability located in outside; 0.1000 probability located in endoplasmic analysis: reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in lysosome (lumen) SignalP Likely cleavage site between residues 24 and 2S
analysis:
A search of the NOVSa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 5C.
Table SC. Geneseq Results for NOVSa NOVSa Identities/
Geneseq Protein/Organism/Length Residues/ Expect Identifier [Patent #, Date] Match similarities for the Value Residues Matched Region No Significant Matches Found In a BLAST search of public sequence databases, the NOVSa protein was found to have homology to the proteins shown in the BLASTP data in Table SD.
Table SD. Public BLASTP Results for NOVSa NOVSa Identities/

Protein Residues/Similarities for Expect AccessionProtein/Organism/LengthMatch the Matched Value Number Residues Portion B60407 monocyte adherence-induced1..52 43/52 (82%) 4e-19 protein 5 alpha - human,1..52 48/52 (91 %) 52 aa.

PFam analysis predicts that the NOVSa protein contains the domains shown in the Table SE.
Table SE. Domain Analysis of NOVSa Identities/
Pfam Domain NOVSa Match Region Similarities Expect Value for the Matched Region No Significant Matches Found EXAMPLE 6.
The NOV6 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 6A.
Table 6A. NOV6 Sequence SEQ ID NO: 23 2305 NOVGa, ATTTTTTCCCCTCGGCTGCCGGCGGCTCCGACATCATGCTCCGGCTCCTCCGGCCGCT

DNA

CTGTCCCCGGGGGCGCCCCCGCAGGCCCCCGACTTGCTCTACGCTGACGGGCTGCGCG

SequeriCe CCTACGCGGCCGGGGCTTGGGCGCCGGCCGTGGCGCTGCTGCGGGAGGCGCTGCGGAG

CCAGGCGGCGCTGGGCCGGGTGCGGCTGGATTGCGGGGCGAGCTGCGCGGCCGATCCG

GGCGCCGCGCTCCCCGCCGTGCTTCTCGGGGCCCCGGAGCCCGACTCCGGGCCGGGAC

CCACGCAGGGGTCCTGGGAGCGACAGCTTCTCCGTGCAGCGCTCCGCCGCGCAGACTG

CCTGACCCAGTGCGCAGCACGGAGGCTGGGCCCCGGGGGCGCGGCGCGGCTTCGCGTG

GGGAGCGCGCTCCGGGACGCCTTCCGCCGTCGGGAGCCCTACAACTACCTGCAGAGGG

CCTATTACCAGTTGAAGAAGCTGGATCTGGCAGCTGCGGCAGCACACACCTTCTTTGT

AGCAAACCCCATGCACCTGCAGATGCGGGAGGACATGGCTAAGTACAGACGAATGTCG

GGAGTTCGGCCCCAGAGCTTCCGGGACCTGGAGACGCCCCCACACTGGGCAGCCTATG

ACACTGGCCTGGAGCTACTGGGGCGCCAGGAGGCAGGACTGGCACTGCCCAGGCTAGA

GGAGGCTCTTCAGGGGAGCCTGGCCCAGATGGAGAGCTGCCGTGCTGACTGTGAGGGG

CCTGAGGAGCAGCAGGGGGCTGAAGAAGAGGAGGATGGGGCTGCGAGCCAGGGGGGCC

TCTATGAGGCCATTGCAGGACACTGGATTCAGGTCCTGCAGTGCCGGCAACGCTGTGT

GGGGGAAGCAGCCACACGCCCTGGTCGCAGCTTCCCTGTCCCAGACTTCCTTCCCAAC

CAGCTGAGGCGGCTACATGAGGCCCATGCTCAGGTGGGCAATCTGTCCCAGGCTATAG

AAAATGTCCTGAGTGTCCTGCTCTTCTACCCGGAGGATGAGGCTGCCAAGAGGGCTCT

GAACCAGTACCAGGCCCAGCTGGGAGAGCCGAGACCTGGCCTCGGACCCAGAGAGGAC

ATCCAGCGCTTCATCCTCCGATCCCTGGGGGAGAAGAGGCAGCTCTACTATGCCATGG

AGCACCTGGGGACCAGCTTCAAGGATCCTGACCCCTGGACCCCTGCAGCTCTCATCCC

TGAGGCACTTAGAGAAAAGCTCAGAGAGGATCAAGAGAAGAGGCCTTGGGACCATGAG

CCCGTGAAGCCAAAGCCCTTGACCTACTGGAAGGATGTCCTTCTCCTGGAGGGTGTGA

CCTTGACCCAGGATTCCAGGCAGCTGAATGGGTCGGAGCGGGCGGTGTTGGATGGGCT

GCTCACCCCAGCCGAGTGTGGGGTGCTGCTGCAGCTGGCTAAGGATGCAGCTGGGGCT

GGAGCCAGGTCTGGCTATCGTGGTCGCCGCTCCCCTCACACCCCCCATGAACGCTTCG

GGGTGCTAAGCTGCTTCTGGAGGTGAGCGAGCGGGTGCGGACCTTGACCCAGGCCTAC
TTCTCCCCGGAACGGCCCCTGCATCTGTCCTTCACCCACCTGGTGTGCCGCAGCGCCA

TAGAAGGAGAGCAAGAGCAGCGCATGGACCTGAGTCACCCAGTGCACGCAGACAACTG
CGTCCTGGACCCTGACACGGGAGAGTGCTGGCGGGAGCCCCCAGCCTACACCTATCGG
GACTACAGCGGACTCCTCTACCTCAACGATGACTTCCAGGGTGGGGACCTGTTCTTCA
CGGAGCCCAACGCCCTCACTGTCACGGCTCGGGTGCGTCCTCGCTGTGGGCGCCTTGT
GGCCTTCAGCTCCGGTGTCGAGAATCCCCATGGGGTGTGGGCCGTGACTCGGGGACGG
CGCTGTGCCCTGGCACTGTGGCACACGTGGGCACCTGAGCACAGGGAGCAGGAGTGGA
TAGAAGCCAAAGAACTGCTGCAGGAGTCACAGGAGGAGGAGGAAGAGGAAGAGGAAGA
AATGCCCAGCAAAGACCCTTCCCCAGAGCCCCCTAGCCGCAGGCACCAGAGGGTCCAA
GACAAGACTGGAAGGGCACCTCGGGTTCGGGAGGAGCTGTGAGTGGCTGAGCCAGCTC
CTTGAGGATGTGGCCACTTGACTTGTGGAAGGCCATCTTGATG
ORF Start: ATG at 36 OltF Stop: TGA at 2244 SEQ ID NO: 24 736 as MW at 81805.SkD
NOV6a, MLRLLRPLLLLLLLPPPGSPEPPGLTQLSPGAPPQAPDLLYADGLRAYAAGAWAPAVA
CGS7887-O1 PrOtelri LLREALRSQAALGRVRLDCGASCAADPGAALPAVLLGAPEPDSGPGPTQGSWERQLLR
AALRRADCLTQCAARRLGPGGAARLRVGSALRDAFRRREPYNYLQRAYYQLKKLDLAA
Sequence ~TFFVANPMHLQMREDMAKYRRMSGVRPQSFRDLETPPHWAAYDTGLELLGRQEA
GLALPRLEEALQGSLAQMESCRADCEGPEEQQGAEEEEDGAASQGGLYEAIAGHWIQV
LQCRQRCVGEAATRPGRSFPVPDFLPNQLRRLHEAHAQVGNLSQAIENVLSVLLFYPE
DEAAKRALNQYQAQLGEPRPGLGPREDIQRFILRSLGEKRQLYYAMEHLGTSFKDPDP
WTPAALIPEALREKLREDQEKRPWDHEPVKPKPLTYWKDVLLLEGVTLTQDSRQLNGS
ERAVLDGLLTPAECGVLLQLAKDAAGAGARSGYRGRRSPHTPHERFEGLTVLKAAQLA
RAGTVGSQGAKLLLEVSERVRTLTQAYFSPERPLHLSFTHLVCRSAIEGEQEQRMDLS
HPVHADNCVLDPDTGECWREPPAYTYRDYSGLLYLNDDFQGGDLFFTEPNALTVTARV
RPRCGRLVAFSSGVENPHGVWAVTRGRRCALALWHTWAPEHREQEWIEAKELLQESQE
EEEEEEEEMPSKDPSPEPPSRRHQRVQDKTGRAPRVREEL
Further analysis of the NOV6a protein yielded the following properties shown in Table 6B.
Table 6B. Protein Sequence Properties NOV6a PSort ' 0.4991 probability located in lysosome (lumen); 0.3700 probability located in analysis: outside; 0.1000 probability located in endoplasmic reticulum (membrane);
0.1000 probability located in endoplasmic reticulum (lumen) SignalP Likely cleavage site between residues 21 and 22 analysis:
A search of the NOV6a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 6C.
Table 6C.
Geneseq Results for NOV6a NOV6a Identities/

Geneseq Protein/Organism/Length Residues/ SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value Residues Region AAB93142Human protein sequence 37..714 314/706 (44%)e-162 SEQ ID

N0:12045 - Homo Sapiens, 35..720 421/706 (59%) 736 aa.

[EP 1074617-A2, 07-FEB-2001 AAB93215 e-161 N0:12194 - Homo Sapiens, 35..720 421/706 (59%) 736 aa.

[EP1074617-A2, 07-FEB-2001]

AAB88373Human membrane or secretory37..714 313/706 (44%) e-161 protein clone PSEC0109 - Homo Sapiens,35..720 421/706 (59%) aa. [EP 1067182-A2, 10-JAN-2001 ]

AAB36392Human tumour suppressor 37..714 312/706 (44%) e-160 Grosl-S

protein SEQ ID N0:4 - Homo35..720 419/706 (59%) Sapiens, 736 aa. [W0200065047-Al, 2000]

AAB36393Mouse tumour suppressor 24..714 308/721 (42%) e-159 Grosl-L

protein SEQ ID N0:6 - Mus 22..722 424/721 (58%) musculus, 747 aa. [W0200065047-A1, 02-NOV-2000]

In a BLAST search of public sequence databases, the NOV6a protein was found to have homology to the proteins shown in the BLASTP data in Table 6D.
Table 6D. Public BLASTP Results for NOV6a NOV6a Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched Value Number ResiduesPortion Q13512 PROTEIN B - Homo Sapiens 186..736551/551 (100%)0.0 (Human), 551 aa. 1..551 551/551 (100%) Q15740 CHROMOSOME 12P13 SEQUENCE,186..736550/551 (99%)0.0 COMPLETE SEQUENCE 1..551 550/551 (99%) (HYPOTHETICAL 62.3 KDA

PROTEIN) - Homo Sapiens (Human), 551 aa.

088836 CHROMOSOME 6 BAC-284H12 190..736477/549 (86%)0.0 (RESEARCH GENETICS MOUSE 1..545 508/549 (91%) BAC LIBRARY) COMPLETE

SEQUENCE (RESEARCH GENETICS

MOUSE BAC LIBRARY) (GENE

RICH CLUSTER, B GENE) -Mus musculus (Mouse), 545 aa.

Q96SL5 CDNA FLJ14774 FIS, CLONE 37..714 314/706 (44%)e-161 NT2RP4000051, WEAKLY SIMILAR35..720 421/706 (59%) TO SYNAPTONEMAL COMPLEX

PROTEIN SC65 - Homo Sapiens (Human), 736 aa.

Q96SK8 CDNA FLJ14791 FIS, CLONE 37..714 313/706 (44%)e-161 NT2RP4001064, WEAKLY SIMILAR35..720 421/706 (59%) PROTEIN SC6S - Homo sapiens (Human), 736 aa.

PFam analysis predicts that the NOV6a protein contains the domains shown in the Table 6E.
Table 6E. Domain Analysis of NOV6a Identities/
Pfam Domain NOV6a Match Region Similarities Expect Value for the Matched Region No Significant Matches Found EXAMPLE 7.
The NOV7 clone was analyzed, and the nucleotide and predicted polypeptide S sequences are shown in Table 7A.
Table 7A. NOV7 Sequence Analysis SEQ ID NO: 2S 372 by NOV7a, _CCATGAACAGCGGCGTGTGCCTGTGTGTGCTGATGGCGGTACTGGCGGCTGGCGCCCT

GCGCCCCGTAGGCAGCTGAGGGTATCGCAGAGAACGGATGGCGAGTCCCGAGCGCACC
SequeriCe TGGGCGCCCTGCTGGCAAGATACATCCAGCAGGCCCGGAAAGGTAAGAATGCTGCCTC
CCCATCCCTCACTTCTGCCCTTGTTCCCAGGCTCCCGATGCTGACCCTCTTCTCTAGC
GCTAGCCTGATGGGGATGACCTCTCTCGGTAGGAAACAAGCAACATGATTTCTGGCGG
TCCTTTGTAGCAATCTGAGAAGGG
ORF Start: ATG at 3 ORF Stop: TGA at 336 SEQ ID NO: 26 111 as MW at 11598.4kD
NOV7a, MNSGVCLCVLMAVLAAGALTQPVPPADPAGSGLQRAEEAPRRQLRVSQRTDGESRAHL
CGS7HHS-O1 PrOteln G~'LARYIQQARKGKNAASPSLTSALVPRLPMLTLFSSASLMGMTSLGRKQAT
Sequence Further analysis of the NOV7a protein yielded the following properties shown in Table 7B.
Table 7B. Protein Sequence Properties NOV7a PSort 0.8200 probability located in outside; 0.1000 probability located in endoplasmic analysis: reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in microbody (peroxisome) SignalP Likely cleavage site between residues 21 and 22 analysis:
A search of the NOV7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 7C.

' Table 7C. Geneseq Results for NOV7a NOV7a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the MatchedValue ResiduesRegion AAE10339Human cholecystolcinin (CCK)1..110 82/113 (72%)1e-35 - Homo sapiens, 136 aa. [W0200168828-A2,22..129 86/113 (75%) 20-SEP-2001 ]

AAB24381Human procholecystokinin 1..110 82/113 (72%)1e-35 amino acid sequence SEQ ID NO:1 - Homo1..108 86/113 (75%) Sapiens, 115 aa. [W0200061192-A2, 19-OCT-2000]

AAY04729Rat brain cholecystokinin 5..110 56/106 (52%)1e-19 precursor amidation region - Rarius 1..104 62/106 (57%) sp, 105 aa.

[W09910361-A1, 04-MAR-1999]

AAB24382Human CCK A amino acid sequence46..91 31/46 (67%)1e-07 CCK-58 SEQ ID N0:2 - Homo 1..41 34/46 (73%) sapiens, 58 aa. [W0200061192-A2, 19-OCT-2000]

In a BLAST
search of public sequence databases, the NOV7a protein was found to have homology to the proteins shown in the BLASTP data in Table 7D.
Table 7D. Public BLASTP Results for NOV7a NOV7a Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the MatchedValue Number Residues Portion P06307 Procholecystokinin precursor1..110 82/113 (72%)4e-35 (CCK) -Homo Sapiens (Human), 115 1..108 86/113 (75%) aa.

P23362 Procholecystokinin precursor1..110 77/113 (68%)3e-32 (CCK) -Macaca fascicularis (Crab 1..108 83/113 (73%) eating macaque) (Cynomolgus monkey), aa.

P01356 Procholecystokinin precursor1..110 66/113 (58%)2e-24 (CCK) -Sus scrofa (Pig), 114 aa. 1..107 73/113 (64%) Q9DCL5 ADULT MALE KIDNEY CDNA, 1..110 63/113 (SS%)1e-22 RIKEN FULL-LENGTH ENRICHED1..108 71/113 (62%) LIBRARY, CLONE:061002501 S, FULL INSERT SEQUENCE -Mus musculus (Mouse), 115 aa.

P09240 Procholecystokinin precursor1..110 62/113 (54%)2e-21 (CCK) -Mus musculus (Mouse), 115 1..108 69/113 (60%) aa.

PFam analysis predicts that the NOV7a protein contains the domains shown in the Table 7E.
Table 7E. Domain Analysis of NOV7a Identities/
Pfam Domain NOV7a Match Region Similarities Expect Value for the Matched Region Gastrin: domain 1 of 1 2..71 37/80 (46%) 7.Se-22 64/80 (80%) EXAMPLE 8.
The NOV8 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 8A.
Table 8A. NOV8 Sequence Analysis SEQ ID NO: 27 479 by NOVBa, TGACTGTATCGCCGGAATTCATGAAGGATCGATTCAAGTGGTTGTCGCTGGAGCTGCT

DNA

AAGCAGCGGGCGAATCAGCCGAATCATGGCAAGGCCCGGAGTCAGCCGGCTCACTCGA

Sequence ATCCGTACGAGGTGGTGGCCGTTGCGCAGACCTACCATCCCGGCCAGCAGATATCGGT

GGTCATCTATCCGCACTCGGACCAGAGCACTGTCTTCCGGGGATTCTTCCTGCAGGCG

CGCGATGCCAACTCGAACGAGTGGATCGGCGAGTGGGTGCAGAGCGAGAACACCAAGA

CCATTCCAGAGTGCTCGGCCATCACGCACTCGGACAACCGGGACAAGCTGGGGGCCAA

GCTCATCTGGAAGGCACCGCAAAATAAGCGGGGACAAGTCTACTTCACGTAACTGCAG

CCAAGCTAATTCCGG

ORF Start: ATG
at 21 ORF Stop:
TAA at 4S6 SEQ ID NO: 28 14S
as MW at 16248.2kD

NOVBa, MKDRFKWLSLELLLLIGAAVAFPDGAPADTCVKQRANQPNHGKARSQPAHSNPYEWA

PTOteln ITHSDNRDKLGAKLIWKAPQNKRGQWFT
Sequence SEQ ID NO: 29 384 by NOVBb, GGATCCTTTCCGGACGGCGCTCCGGCGGACACGTGCGTGAAGCAGCGGGCGAATCAGC

CGTTGCGCAGACCTACCATCCCGGCCAGCAGATATCGGTGGTCATCTATCCGCACTCG

SequeriCe GACCAGAGCACTGTCTTCCGGGGATTCTTCCTGCAGGCGCGCGATGCCAACTCGAACG

AGTGGATCGGCGAGTGGGTGTAGAGCGAGAACACCAAGACCATTCCAGAGTGCTCGGC

CATCACGCACTCGGACAACCGGGACAAGCTGGGGGCCAAGCTCATCTGGAAGGCACCG

CAAAATAAGCGGGGACAAGTCTACTTCACGCTCGAG

ORF Start: GGA OIRF
at 1 Stop:
TAG
at 2S3 SEQ ID NO: 30 84 as MW at 926S.11cD

NOVBb, GSFPDGAPADTCVKQRANQPNHGKARSQPAHSNPYEWAVAQTYHPGQQISWIYPHS

1716S1S32 PrOtelnDQSTVFRGFFLQARDANSNEWIGEWV

Sequence Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 8B.

Table 8B. Comparison of NOVBa against NOVBb and NOVBc.
Protein Sequence NOVBa Residues/ Identities/
Match Residues Similarities for the Matched Region NOVBb 21..103 82/83 (98%) 2..84 83/83 (99%) Further analysis of the NOVBa protein yielded the following properties shown in Table 8C.
Table 8C. Protein Sequence Properties NOVBa PSort 0.6377 probability located in outside; 0.1821 probability located in microbody analysis: (peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane);
0.1000 probability located in endoplasmic reticulum (lumen) SignalP Likely cleavage site between residues 22 and 23 analysis:
A search of the NOV8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 8D.
Table 8D. Geneseq Results for NOVBa NOVBa Identities/
Geneseq Protein/Organism/Length Residues/ Expect Similarities for the Identifier [Patent #, Date] Match Value Residues Matched Region No Significant Matches Found In a BLAST search of public sequence databases, the NOVBa protein was found to have homology to the proteins shown in the BLASTP data in Table 8E.
Table 8E. Public BLASTP Results for NOVBa NOVBa Identities/
Protein Residues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number Residues Portion Q9VAN1 CG14515 PROTEIN - Drosophila 1..145 144/145 (99%) 6e-82 melanogaster (Fruit fly), 145 aa. 1..145 144/145 (99%) PFam analysis predicts that the NOVBa protein contains the domains shown in the Table 8F.
Table 8F. Domain Analysis of NOVBa Pfam Domain ( NOVBa Match Region ~ i Expect Value Similarities for the Matched Region Reefer: domain 30..145 31/150 (21%) 2.8e-05 1 of 1 78/150 (52%) EXAMPLE 9.
The NOV9 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 9A.
Table 9A. NOV9 Sequence Analysis SEQ ID NO: 31 ~ 669 by NOV9a, TCCCGCGGGCCAGCGCACTACGAGATGCTGGGTCGCTGCCGCATGGTGTGCGACCCGC

AGGCGCCAAGGGAGAGGTGGGCCGGCGCGGGAAAGCAGGCCTGCGGGGGCCCCCTGGA
SequeriCe CCACCAGGTCCAAGAGGGCCCCCAGGAGAACCCGGCAGGCCAGGCCCCCCGGGCCCTC
CCGGTCCAGGTCCGGGCGGGGTGGCGCCCGCTGCCGGCTACGTGCCTCGCATTGCTTT
CTACGCGGGCCTGCGGCGGCCCCACGAGGGTTACGAGGTGCTGCGCTTCGACGACGTG
GTGACCAACGTGGGCAACGCCTACGAGGCAGCCAGCGGCAAGTTTACTTGCCCCATGC
CAGGCGTCTACTTCTTCGCTTACCACGTGCTCATGCGCGGCGGCGACGGCACCAGCAT
GTGGGCCGACCTCATGAAGAACGGACAGGTCCGGGCCAGCGCCATTGCTCAGGACGCG
GACCAGAACTACGACTACGCCAGCAACAGCGTCATTCTGCACCTGGACGTGGGCGACG
AGGTCTTCATCAAGCTGGACGGCGGGAA.AGTGCACGGCGGCAACACCAACAAGTACAG
CACCTTCTCCGGCTTCATCATCTACCCCGAC
ORF Start: TCC at 1 ORF Stop: th at 670 SEQ ID NO: 32 223 as MW at 23296.11cD
NOV9a, SRGPAHYEMLGRCRMVCDPHGPRGPGPDGAPASVPPFPPGAKGEVGRRGKAGLRGPPG
CGS4SO3-O3 PrOteln PPGPRGPPGEPGRPGPPGPPGPGPGGVAPAAGYVPRIAFYAGLRRPHEGYEVLRFDDV
Se uenCe VTNVGNAYEAASGKFTCPMPGVYFFAYHVLMRGGDGTSMWADLMKNGQVRASAIAQDA
q DQNYDYASNSVILHLDVGDEVFIKLDGGKVHGGNTNKYSTFSGFIIYPD
Further analysis of the NOV9a protein yielded the following properties shown in Table 9B.
Table 9B. Protein Sequence Properties NOV9a PSort 0.8276 probability located in lysosome (lumen); 0.4500 probability located in analysis: cytoplasm; 0.4128 probability located in microbody (peroxisome);
0.1000 probability located in mitochondrial matrix space SignalP No Known Signal Sequence Predicted analysis:
A search of the NOV9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 9C.
Table 9C. Geneseq Results for NOV9a Geneseq Protein/Organism/Length [Patent NOV9a Identities/ Expect Identifier #, Date] Value Match the Matched ResiduesRegion AAG64212 Murine HSP47 interacting 5..223 169/236 (71 l e-91 protein, %) #2 - Mus sp, 255 aa. [JP2001145493-20..255 183/236 (76%) A, 29-MAY-2001 ]

AAM40913 Human polypeptide SEQ 19..222 90/242 (37%)2e-32 ID NO

5844 - Homo Sapiens, 755 519..754121/242 (49%) aa.

[W0200153312-A1, 26-JUL-2001]

AAM39127 Human polypeptide SEQ 19..222 90/242 (37%)2e-32 ID NO

2272 - Homo Sapiens, 744 508..743121/242 (49%) aa.

[W0200153312-A1, 26-JUL-2001]

AAM40607 Human polypeptide SEQ 19..223 82/218 (37%)3e-30 ID NO

5538 - Homo Sapiens, 255 43..252 112/218 (SO%) aa.

[W0200153312-A1, 26-JL1L-2001]

AAM38821 Human polypeptide SEQ 19..223 82/218 (37%)3e-30 ID NO

1966 - Homo Sapiens, 253 41..250 112/218 (50%) aa.

[W0200153312-Al, 26-JLTL-2001]

In a BLAST search of public sequence databases, the NOV9a protein was found to have homology to the proteins shown in the BLASTP data in Table 9D.
Table 9D. Public BLASTP Results for NOV9a NOV9a Identities/

Protein Residues/Similarities Expect for AccessionProtein/Organism/Length Match the Matched Value Number ResiduesPortion 088992 Clq-related factor precursor1..223 171/244 (70%)2e-93 - Mus musculus (Mouse), 258 15..258 183/244 (74%) aa.

075973 C 1 q-related factor 1..223 174/244 (71 4e-93 precursor - %) Homo Sapiens (Human), 15..258 185/244 (75%) 258 aa.

Q9ESN4 Gliacolin precursor - 5..223 169/236 (71%)Se-91 Mus musculus (Mouse), 255 aa. 20..255 183/236 (76%) Q921S8 PROCOLLAGEN, TYPE VIII, 19..222 94/241 (39%) 3e-34 ALPHA 1 - Mus musculus 509..743123/241 (51%) (Mouse), 744 aa.

Q9D2V4 PROCOLLAGEN, TYPE VIII, 19..222 94/241 (39%) 3e-34 ALPHA 1 - Mus musculus 509..743123/241 (51%) (Mouse), 744 aa.

PFam analysis predicts that the NOV9a protein contains the domains shown in the Table 9E.
Table 9E. Domain Analysis of NOV9a Identities/
Pfam Domain NOV9a Match Region Similarities Expect Value for the Matched Region Collagen: domain 1 of 1 35..92 36/60 (60%) 0.0043 49/60 (82%) C 1 q: domain 1 of 1 96..220 43/ 140 (31 %) 6.4e-29 92/140 (66%) EXAMPLE 10.
The NOV10 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 10A.
Table 10A. NOV10 Sequence Analysis SEQ ID NO: 33 ~ 1642 NOVIOa, _TCTCAAGTGAATACCCTGATTTCCTTCCTTCCTTCTTTCCTTTCCTTTCCTCCTCCTC

CTGGTGAGAAGTGTGTCAAGCTCTGTGGATGAAGGAGGCACATGCCATTGTATGGTTC
SeqlleriCe ACCTACCCAACAACCCCATCCCCCTGGAGCAGCTGGAACAGCTACAAAGTACAGCTCA
GGAGCTCATTTGCAAGTATGAGCAGAAGCTGTCTAGAGTCAGTGAGTGTGCACGCGCC
ATTGAAGATAAAGACAATGAGGTTCTGGAAATGAGTCACATGCTGAAGTCCTGGAATC
CCAGTGCCCTTGCTTCTCCCTATGAGAACCCAGGCTTCAACCTGCTGTGCCTGGAGCT
GGAGGGAGCACAGGAGTTGGTGACTCAACTTAAAGCCATGGGAGGTGTTAGTGTGGCT
GGGGACCTCCTCCACCAACTTCAGAGCCAGGTGACTAACGCCAGTCTCACACTCAAAC
TTTTGGCTGACTCTGACCAGTGCAGCTTTGGTGCTCTCCAGCAGGAGGTGGATGTCCT
TGAGAAAAGAAAAGTAGAAAGATTTTTAAAAATTAAGACAAAAAATAGGCCGAAAATA
CACTTTCCACCTGCTATGAATTCTTGTGCCCATGGAGGCCTCCAGGAAGTTAGCAAAT
CCCTTGTGGTGCAGCTCACTCGGAGAGGCTTCTCATATAAGGCAGGTCCCTGGGGCCG
AGACTCAGCACCCAATCCAGCCTCTTCCCTTTACTGGGTTGCTCCTCTACGTACAGAT
GGCAGGTACTTTGACTACTATCGGCTGTGCAAATCCTATAATGACCTCGCACTGCTGA
AAAACTATGAAGAGAGGAAGATGGGCTATGGTGATGGCAGTGGAAACGTTGTGTACAA
GAACTTTATGTACTTTAACTACTGTGGCACAAGTGACATGGCCAAAATGGACCTTTCC
TCCAACACACTGGTGCTGTGGCGTCTGCTGCCTGGTGCCACCTATAACAACCGCTTTT
CCTGTGCTGGTGTGCCCTGGAAGGACTTAGATTTTGCTGGTGATGAGAAGGGGCTGTG
GGTTCTGTATGCCACTGAGGAGAGCAAGGGCAACCTGGTTGTGAGTCGTCTCAACGCT
AGCACCCTAGAAGTGGAGAAAACCTGGCGTACCAGCCAGTACAAGCCAGCCCTGTCAG
GGGCCTTCATGGCCTGTGGGGTGCTCTATGCCTTACACTCACTGAACACCCACCAAGA
GGAGATCTTCTATGCTTTTGACACCACCACCGGGCAGGAGCGCCGCCTCAGCATCCTG
TTGGACAAGATGCTGGAAAAGCTGCAGGGCATCAACTACTGCCCCTCAGACCACAAGC
CGTATGTCTTCAGTGATGGTTACCTGATAAATTATGACCTCACCTTCCTGACAATGAA
GACCAGGCTACCAAGACCACCCACCAGGAGGCCCTCTGGGGCTCATGCTCCACCAAAA
CCTGTCAAACCTAACGAGGCTTCCAGACCCTGAGACCCCAGGGCTAGGCAGAGCATTG
GTAGAAGTGTGCCCTCTTCCTTACCTCCAGGAGGACCACATCCCAAAGTGGCCATTGG
TCCTAATGATTGGAAGAC
ORF Start: TCA at 3 OIRF Stop: TGA at 1 S39 SEQ ID NO: 34 ~~S 12 as MW at S72S 1.3lcD
NOVIOa, SSEYPDFLPSFFPFLSSSSTFSSPSPSSSSSLPSFPSQLVRSVSSSVDEGGTCHCMVH
CGS86OO-O1 PrOteln LPNNPIPLEQLEQLQSTAQELICKYEQKLSRVSECARAIEDKDNEVLEMSHMLKSWNP
S8 uenCB S~ASPYENPGFNLLCLELEGAQELVTQLKAMGGVSVAGDLLHQLQSQVTNASLTLKL
q LADSDQCSFGALQQEVDVLEKRKVERFLKIKTKNRPKIHFPPAMNSCAHGGLQEVSKS
LWQLTRRGFSYKAGPWGRDSAPNPASSLYWVAPLRTDGRYFDYYRLCKSYNDLALLK
NYEERKMGYGDGSGNWYKNFMYFNYCGTSDMAKMDLSSNTLVLWRLLPGATYNNRFS
CAGVPWKDLDFAGDEKGLWVLYATEESKGNLWSRLNASTLEVEKTWRTSQYKPALSG
AFMACGVLYALHSLNTHQEEIFYAFDTTTGQERRLSILLDKMLEKLQGINYCPSDHKP

YVFSDGYLINYDLTFLTMKTRLPRPPTRRPSGAHAPPKPVKPNEASRP
Further analysis of the NOV 10a protein yielded the following properties shown in Table IOB.
Table 10B. Protein Sequence Properties NOVlOa PSort 0.3700 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1800 probability located in nucleus; 0.1000 probability located in endoplasmic reticulum (membrane) SignalP No Known Signal Sequence Predicted analysis:
A search of the NOV 10a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table IOC.
Table IOC. Geneseq Results for NOVlOa NOVlOa Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value ResiduesRegion AAY54368 Protein encoded by colon 5..480 219/482 (45%)e-114 specific gene (CSG) clone 2348122 - Homo32..506 310/482 (63%) sapiens, 510 aa. [W09960161-A1, 1999]

AAY22201 Human extracellular mucous5..480 219/482 (45%)e-114 matrix glycoprotein protein sequence32..506 310/482 (63%) - Homo Sapiens, 510 aa. [US5929033-A, JUL-1999]

AAE03653 Human extracellular matrix10..480 217/477 (45%)e-114 and cell adhesion molecule-17 (XMAD-17)35..506 308/477 (64%) -Homo sapiens, S 10 aa.

[W0200142285-A2, 14-JLTN-2001 ]

AAB50955 Human PR0698 protein - 10..480 217/477 (45%)e-114 Homo Sapiens, 510 aa. [W0200073348-A2,35..506 308/477 (64%) 07-DEC-2000]

AAB65169 Human PR0698 (UNQ362) protein10..480 217/477 (45%)e-114 sequence SEQ ID N0:67 - 35..506 308/477 (64%) Homo sapiens, 510 aa. [W0200073454-A1, 07-DEC-2000]

In a BLAST 10a protein search was found of public to sequence databases, the NOV

have homology to the proteins shown data in the BLASTP in Table l OD.

Table 10D. Public BLASTP Results for NOVlOa NOVlOa Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched Value Number Residues Portion Q9H1L6 BA209J19.1.1 (GW112 PROTEIN)10..480 217/477 (45%)e-113 - Homo Sapiens (Human), 35..506 308/477 (64%) 510 aa.

Q07081 Olfactomedin precursor 53..477 1 SS/441 2e-68 (Olfactory (35%) mucus protein) - Rana 32..460 247/441 (55%) catesbeiana (Bull frog), 464 aa.

AAL66227 NOELIN-1 - Xenopus laevis28..478 114/458 (24%)1e-32 (African clawed frog), 48..475 194/458 (41%) 485 aa.

AAL66226 NOELIN-2 - Xenopus laevis32..478 113/454 (24%)3e-32 (African clawed frog), 25..448 192/454 (41%) 458 aa.

095362 GW112 PROTEIN - Homo 139..315 77/178 (43%)7e-32 Sapiens (Human), 187 aa. 2..176 107/178 (59%) PFam analysis predicts that in the NOVlOa protein contains the the domains shown Table 10E.
Table 10E. Domain Analysis of NOVlOa Identities/
Pfam Domain NOVlOa Match Region Similarities Expect Value for the Matched Region OLF: domain 1 of 1 224..481 93/294 (32%) 8.1e-72 170/294 (58%) EXAMPLE 11.
The NOV 11 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 11 A.
Table 11A. NOVIl Sequence Analysis SEQ ID NO: 35 1134 by NOVlla, GCAGAAGAATAGGCTACTTTATTTTCTGAAAAGGAGGGAGTTCCTGCCACCCATTGCA

GCTCACCTTCCTCGTGCTCTTCATCTTCCTCACCTCCTTCCTGAACTACTCCCACGCC
Sequence ATGGTGGCCACCACCTGGTTCCCCAAGAAGATGGCCCTGGAGCTCTTGGAGAACCTGA
AGAGACTGATCAAGCACAGGCCCTGCACTTGCACCCACTGCATCAGGCAGCATGGGCT
CTCAGCCTGGTTCGATGAGAGGTTCAACCAGATAGTGCAGCTGCTGCTGACTGCCCAG
AACGCGCTCTTGGAGGACAACACCTACCAATGGTGGCTGAGGCTCCAGCAGGAGAAGA
AGCCCAATATCATCAACAATACCATCAAGGAATTCAGAGCAGTACCTGGGAATGTGGA
CCCAATGCTGGAGAAGAGGTCGGTGGGCTGCTGGCACTGTGCTGTCGTGGGCAACTCG
GGCAACCTGAGGCAATTGTCATATCACAATTTTATGCTCAGGATGAACAAGGCACCCA
CGGCAGGGTTTGAAGCTGCTGCCGGGAGCAAAACCGCCCACCATCTGGTGTACCCTGA
GAGCTTCCGGGAGCTGGGGGACAATGTCAGCATGGTCCTGGTGCCCTTAAAGACCATG
AACTTGGAGTGGGTGGTGAGCACCACCACCACGGGTGCCATTTCCCACACCTACACCC

CGGTCCTCGTGAAGATCAGAGTGAAACAGGATAAGATCCTGATCTACCACCCAGCCTT

CATCAAGTATGTCTTCGACAACTGGCTGCAGAGCCACAGGCGGTACCCACTCACCAGC

ATCCTCTCGGTCATCTTCTCAATGCATGTCTGCGATAAGGTAGACTTGTATAGCTTCG

GAGCAGATAGCAAAGGGAACTGGCACCACTACTGGGAGAACAACCTGTCTGCGGGGTC

TTTTCACAAGACGGGGGTGCACGATGCAGGCTTTGAGTCTAACGTGACGGCCACCTTG

GCTTCATCAATAAAATCCCGATCTTCAAGGGGAGATGACACAGTGAAGGGGTGAGGAT

GGATGCCCCATCATGCCTCTGCGTTTCAAGCC

ORF Start: ATG ORF Stop:
at 8S TGA
at 1096 SEQ ID NO: 36 337 as MW at 38SS9.2kD

NOVlla, MVTLRKRTLKVLTFLVLFIFLTSFLNYSHAMVATTWFPKKMALELLENLKRLIKHRPC

PTOtelri KEFRAVPGNVDPMLEKRSVGCWHCAWGNSGNLRQLSYHNFMLRMNKAPTAGFEAAAG
Sequence SKTAHHLVYPESFRELGDNVSMVLVPLKTMNLEWWSTTTTGAISHTYTPVI~VKIRVK

QDKILIYHPAFIKYVFDNWLQSHRRYPLTSILSVIFSMHVCDKVDLYSFGADSKGNWH

HYWENNLSAGSFHKTGVHDAGFESNVTATLASSIKSRSSRGDDTVKG

Further analysis of the NOV1 la protein yielded the following properties shown in Table 11B.
Table 11B. Protein Sequence Properties NOVlla PSort 0.8200 probability located in outside; O.SOS4 probability located in lysosome analysis: (lumen); O.1S6S probability located in microbody (peroxisome);
0.1000 probability located in endoplasmic reticulum (membrane) SignalP Likely cleavage site between residues 31 and 32 analysis:
A search of the NOV 11 a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 11C.
Table 11C. Geneseq Results for NOVlla NOVIla Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value ResiduesRegion AAR6S244Human ST30 sialyltransferase1..331 274/339 (80%)e-1 - Homo S8 sapiens, 340 aa. [W09S04816-A,1..339 292/339 (8S%) FEB-1995]

AAR6S240Porcine ST30 sialyltransferase5..331 234/337 (69%)e-137 - Sus scrofa, 343 aa. [W09S04816-A,6..342 272/337 (80%) FEB-1995]

AAR41670Porcine sialyltransferase 5..331 234/337 (69%)e-137 - Sus scrofa, 343 aa. [W093181 S7-A, 6..342 272/337 (80%) 1993]

AAR7S198Rat Gal-beta-l,3GalNAc,alpha-2,3-12..332 149/341 (43%)6e-78 12..350 203/341 (S8%) norvegicus, 350 aa. [JP07236477-A, 12-SEP-1995]

AAR75200Rat P-F4M active fragment,50..332 135/290 (46%)3e-76 - Rattus norvegicus, 314 26..314 183/290 (62%) aa.

[JP07236477-A, 12-SEP-1995]

In a BLAST search of public sequence databases, the NOV 11 a protein was found to have homology to the proteins shown in the BLASTP data in Table 11D.
Table 11D. Public BLASTP Results for NOVlla Protein NOVlla Identities/

AccessionProtein/Organism/Length Residues/SimilaritiesExpect for Number Match the Matched Value ResiduesPortion Q11201 CMP-N-acetylneuraminate-beta-1..331 278/339 (82%)e-160 galactosamide-alpha-2, 3-sialyltransferase1..339 295/339 (87%) (EC 2.4.99.4) (Beta-galactoside alpha-2,3-sialyltransferase) (Alpha 2,3-ST) (Gal-NAC6S) (Gal-beta-1,3-GaINAc-alpha-2,3-sialyltransferase) (ST3GALIA) (ST30) (ST3GALA.1) (SIAT4-A) -Homo sapiens (Human), 340 aa.

Q9UN51 ALPHA-2,3-SIALYLTRANSFERASE1..331 276/339 (81%)e-159 -Homo Sapiens (Human), 340 1..339 294/339 (86%) aa.

P54751 CMP-N-acetylneuraminate-beta-4..331 230/336 (68%)e-137 galactosamide-alpha-2, 3-sialyltransferase1..336 273/336 (80%) (EC 2.4.99.4) (Beta-galactoside alpha-2,3-sialyltransferase) (Alpha 2,3-ST) (GAL-NAC6S) (GAL-beta-1,3-GALNAC-alpha-2,3-sialyltransferase) (ST3GALIA) (ST30) (ST3GALA.1) (SIAT4-A) - Mus musculus (Mouse), 337 aa.

A45073 Gal beta l,3GalNAc alpha 5..331 234/337 (69%)e-137 2,3-sialyltransferase - pig, 6..342 272/337 (80%) 343 aa.

Q02745 CMP-N-acetylneuraminate-beta-5..331 234/337 (69%)e-136 galactosamide-alpha-2, 3-sialyltransferase6..342 272/337 (80%) (EC 2.4.99.4) (Beta-galactoside alpha-2,3-sialyltransferase) (Alpha 2,3-ST) (GAL-NAC6S) (GAL-beta-1,3-GALNAC-alpha-2,3-sialyltransferase) (ST3GALIA) (ST30) (ST3GALA.1) (SIAT4-A) - Sus scrofa (Pig), 343 aa.

PFam analysis predicts that the NOV 11 a protein contains the domains shown in the Table 11 E.

Table 11E. Domain Analysis of NOVlla Identities/

Pfam Domain NOVIla Match Similarities Expect Region for the Matched Value Region IF3: domain 1 of 6/10 (60%) 6.3 1 193..202 9/10 (90%) transf_29: domain 97/324 (30%) 4.7e-73 1 60..331 Glyco _ 223/324 (69%) of 1 EXAMPLE 12.

The NOV 12 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 12A.
Table 12A. NOV12 Sequence Analysis SEQ ID NO: 37 X4295 by NOVl2a, TCTTCGTCGCCGCTCTCTCTCTCACCTCTCAGGGAAAGGGGGGGACATAGGGGCGTCG

DNA

GAAGCACCGGCCGTGAAGATGGAGGTGACCTGCCTTCTACTTCTGGCGCTGATCCCCT
SequeriCe TCCACTGCCGGGGACAAGGAGTCTACGCTCCAGCCCAGGCGCAGATCGTGCATGCGGG

CCAGGCATGTGTGGTGAAAGAGGACAATATCAGCGAGCGTGTCTACACCATCCGGGAG

GGGGACACCCTCATGCTGCAGTGCCTTGTAACAGGGCACCCTCGACCCCAGGTACGGT

GGACCAAGACGGCAGGTAGCGCCTCGGACAAGTTCCAGGAGACATCGGTGTTCAACGA

GACGCTGCGCATCGAGCGTATTGCACGCACGCAGGGCGGCCGCTACTACTGCAAGGCT

GAGAACGGCGTGGGGGTGCCGGCCATCAAGTCCATCCGCGTGGACGTGCAGTACCTGG

ATGAGCCAATGCTGACGGTGCACCAGACGGTGAGCGATGTGCGAGGCAACTTCTACCA

GGAGAAGACGGTGTTCCTGCGCTGTACTGTCAACTCCAACCCGCCTGCCCGCTTCATC

TGGAAGCGGGGTTCCGATACCCTATCCCACAGCCAGGACAATGGGGTTGACATCTATG

AGCCCCTCTACACTCAGGGGGAGACCAAGGTCCTGAAGCTGAAGAACCTGCGGCCCCA

GGACTATGCCAGCTACACCTGCCAGGTGTCTGTGCGTAACGTGTGCGGCATCCCAGAC

AAGGCCATCACCTTCCGGCTCACCAACACCACGGCACCACCAGCCCTGAAGCTGTCTG

AGGCGGTGATCCCCTCCCCCAGCTGCAGTGGTCCCATGGGCCTGGCCCACTGCCCCTG
GGTGCTCTGGCCCAGGGTGGCACCCTCAGCATCCCTTCAGTGCAGGCCCGGGACTCTG
GCTACTACAACTGCACAGCCACCAACAATGTGGGCAACCCTGCCAAGAAGACTGTCAA
CCTGCTGGTGCGATCCATGAAGAACGCTACATTCCAGATCACTCCTGACGTGATCAAA
GAGAGTGAGAACATCCAGCTGGGCCAGGACCTGAAGCTATCGTGCCACGTGGATGCAG
TGCCCCAGGAGAAGGTGACCTACCAGTGGTTCAAGAATGGCAAGCCGGCACGCATGTC
CAAGCGGCTGCTGGTGACCCGCAATGATCCTGAGCTGCCCGCAGTCACCAGCAGCCTA
GAGCTCATTGACCTGCACTTCAGTGACTATGGCACCTACCTGTGCATGGCTTCTTTCC
CAGGGGCACCCGTGCCCGACCTCAGCGTCGAGGTCAACATCTCCTCTGAGACAGTGCC
GCCCACCATCAGTGTGCCCAAGGGTAGGGCCGTGGTGACCGTGCGCGAGGGATCGCCT
GCCGAGCTGCAATGCGAGGTGCGGGGCAAGCCGCGGCCGCCAGTGCTCTGGTCCCGCG
TGGACAAGGAGGCTGCACTGCTGCCCTCGGGGCTGCCCCTGGAGGAGACTCCGGACGG
GAAGCTGCGGCTGGAGCGAGTGAGCCGAGACATGAGCGGGACCTACCGCTGCCAGACG
GCCCGCTATAATGGCTTCAACGTGCGCCCCCGTGAGGCCCAGGTGCAGCTGAACGTGC
AGTTCCCGCCGGAGGTGGAGCCCAGTTCCCAGGACGTGCGCCAGGCGCTGGGCCGGCC
CGTGCTCCTGCGCTGCTCGCTGCTGCGAGGCAGCCCCCAGCGCATCGCCTCGGCTGTG
CGCCGGATCACGCGGAGCTGCGCCTCGACGCCGTAACTCGCGACAGCAGCGGCAGCTA
CGAGTGCAGCGTCTCCAACGATGTGGGCTCGGCTGCCTGCCTCTTCCAGGTCTCCGCC
AAAGCCTACAGCCCGGAGTATTACTTCGACACCCCCAACCCCACCCGCAGCCACAAGC
TGTCCAAGAACTACTCCTACGTGCTGCAGTGGACTCAGAGGGAGCCCGACGCTGTCGA

CCCTGTGCTCAACTACAGACTCAGCATCCGCCAGTTGAACCAGCACAATGCGGTGGTC

AAGGCCATCCCGGTCCGGCGTGTGGAGAAGGGGCAGCTGCTGGAGTACATCCTGACCG

ATCTCCGTGTGCCCCACAGCTATGAGGTCCGCCTCACACCCTATACCACCTTCGGGGC

TGGTGACATGGCCTCCCGCATCATCCACTACACAGAGCGCCAGATCCGCTGGCCCCCA

GTCCTGGCTCTGAGGACCCTGTCCTCTGGTCCCAAGCAGGGTATCCTCTGCAGAGCCC

CACACCTCAGTTCTGACTTGGTTTCCCCGCTTGCTTTCTCAGCCATCAACTCTCCGAA

CCTTTCAGACAACACCTGCCACTTTGAGGATGAGAAGATCTGTGGCTATACCCAGGAC

CTGACAGACAACTTTGACTGGACGCGGCAGAATGCCCTCACCCAGAACCCCAAACGCT

CCCCCAACACTGGTCCCCCCACCGACATAAGTGGCACCCCTGAGGGCTACTACATGTT

CATCGAGACATCGAGGCCTCGGGAGCTGGGGGACCGTGCAAGGTTAGTGAGTCCCCTC

TACAATGCCAGCGCCAAGTTCTACTGTGTCTCCTTCTTCTACCACATGTACGGGAAAC

ACATCGGCTCCCTCAACCTCCTGGTGCGGTCCCGGAACAAAGGGGCTCTGGACACGCA

CGCCTGGTCTCTCAGTGGCAATAAGGGCAATGTGTGGCAGCAGGCCCATGTGCCCATC

AGCCCCAGTGGGCCCTTCCAGATTATTTTTGAGGGGGTTCGAGGCCCGGGCTACCTGG

GGGATATTGCCATAGATGACGTCACACTGAAGAAGGGGGAGTGTCCCCGGAAGCAGAC

GGATCCCAATAAAGGTGCAAGACGGGAAGGAGCTGCCTGCGATGGCCTGAAATTCCAC

CTTTCATCCCCTATGGATGACGGAGAGCTTACAGATGACCCTATTGAATGCAAGCACC

TTTGGATCCATAGAGTGGACAGTAAAGGTGCTCAGTACATGTTGGCTGAGCTGAACTG

CATACATGTGGCCCCCAGGTTCCTGGTCTTTATGGACGAAGGGCACAAGGTTGGTGAA

AAGGACTCCGGGGGCCAGCCCTTCCAAGTTTACACTGATTTCTCCTTTTACCCTCATG

CTATCCCTGAGAAGATGTCAATAATGCCCACGTTACAGGTGGGAAAACTGAGGCTTAG

AGAGGAGGAGGAATCTGCCTACGGTCACACAGCTGCAAAGGCTAGAGCTGGGACCAGG

AGCTGGTCTCTTAACCGACCACCTGAGCTCAAGAGCTTTTCTCTCTGGACCAACATGA

CCCAAAGTGTGCGCGAGCCTATCACAGGTCCCCTGCAATGCCAAACATACACGCACAG

CAATACACAACACCTGGGGACATGGATGAAGCTGGAAACCATCATTCTCAGCAAACTG

ACACAAGAACAGAAAACCAAACACCACATGTTCTCACTCACCACCCAGTCTGCCCCGC

CCTCTCTCTTCTCACCTGAACTTCCCCTCTCCTCAAACTCTCGAGGCCACGCCTCTAT

GTCCTTGGATGATGATGATGACGACGACGACGATGATGATGATGATGATGACGACGAT

GACAATGATGATGATGATGGAAGGAAGACCTACAGAATCCCTCCAGGCTCTGACCTCA

GTGCTTGTGGGTGGGTGAATGACCACATGTCGCAGGGAGACTCCACAGGTCCTCCCGA

TGAGAAGCACTCTTATGCCAAAGAGGAGACTCAGGCCAAACTGACAGGACCAGGAATT

AGCTACCCTGGTAAACCCAGCTATCGACTGCACCCGAGCGGCTACACACCACTGGAGC

AGTTCAGGGAGAAAGCCACCGGCATGCTCACCCCGTATGTCTCTGGCTCTGTTTCCTC

TTTCTGCTTCCCCTTCCCCACCTCTGAGTCTCTGTGTTCTGCTCATGCCAATTCCCCT

TCTGCCTGTCTCTGCCCGCTTCTCTCTCTGGGCTGGTCTCTCCGAGACTCTGTTCCCT

TGGCTGGCATGCCCTCCACCTCCCCTGATGCTGGAGCAGTTCAGGGAGAAAGCCACCG

GCATGCTCACCGTATGTCTCTGGCTCTGTTTCCTCTTTCTGCTTCCCCTTCCCCACCT

TGA

ORF Start: ATG ORF Stop:
at 135 TGA at SEQ ID NO: 38 1386 as MW at 153195.2kD

NOVl2a, MEVTCLLLLALIPFHCRGQGWAPAQAQIVHAGQACWKEDNISERVYTIREGDTLML

Protein S8C111eI1Ce PAIKSIRVDVQYLDEPMLTVHQTVSDVRGNFYQEKTVFLRCTVNSNPPARFIWKRGSD

TLSHSQDNGVDIYEPLYTQGETKVLKLKNLRPQDYASYTCQVSVRNVCGIPDKAITFR

LTNTTAPPALKLSVNETLVVNPGENVTVQCLLTGGDPLPQLQWSHGPGPLPLGALAQG

GTLSIPSVQARDSGYYNCTATNNVGNPAKKTVNLLVRSMKNATFQITPDVIKESENIQ

LGQDLKLSCHVDAVPQEKVTYQWFKNGKPARMSKRLLVTRNDPELPAVTSSLELIDLH

FSDYGTYLCMASFPGAPVPDLSVEVNISSETVPPTISVPKGRAVVTVREGSPAELQCE

VRGKPRPPVLWSRVDKEAALLPSGLPLEETPDGKLRLERVSRDMSGTYRCQTARYNGF

NVRPREAQVQLNVQFPPEVEPSSQDVRQALGRPVLLRCSLLRGSPQRIASAVWRFKGQ

LLPPPPWPAAAEAPDHAELRLDAVTRDSSGSYECSVSNDVGSAACLFQVSAKAYSPE

IYFDTPNPTRSHKLSKNYSYVLQWTQREPDAVDPVLNYRLSIRQLNQHNAWKAIPVR

RVEKGQLLEYILTDLRVPHSYEVRLTPYTTFGAGDMASRIIHYTERQIRWPPVLALRT

LSSGPKQGILCRAPHLSSDLVSPLAFSAINSPNLSDNTCHFEDEKICGYTQDLTDNFD

WTRQNALTQNPKRSPNTGPPTDISGTPEGYYMFIETSRPRELGDRARLVSPLYNASAK

FYCVSFFYHMYGKHIGSLNLLVRSRNKGALDTHAWSLSGNKGNVWQQAHVPISPSGPF

QIIFEGVRGPGYLGDIAIDDVTLKKGECPRKQTDPNKGARREGAACDGLKFHLSSPMD

DGELTDDPIECKHLWIHRVDSKGAQYMLAELNCIHVAPRFLVFMDEGHKVGEKDSGGQ

PFQWTDFSFYPHAIPEKMSIMPTLQVGKLRLREEEESAYGHTAAKARAGTRSWSLNR

PPELKSFSLWTNMTQSVREPITGPLQCQTYTHSNTQHLGTWMKLETIILSKLTQEQKT

KHHMFSLTTQSAPPSLFSPELPLSSNSRGHASMSLDDDDDDDDDDDDDDDDDDNDDDD

GRKTYRIPPGSDLSACGWVNDHMSQGDSTGPPDEKHSYAKEETQAKLTGPGISYPGKP

SYRLHPSGYTPLEQFREKATGMLTPYVSGSVSSFCFPFPTSESLCSAHANSPSACLCP

LLSLGWSLRDSVPLAGMPSTSPDAGAVQGESHRHAHRMSLALFPLSASPSPP

SEQ ID NO: 39 906 by NOVl2b, GGTACCCCACCAGCCCTGAAGCTGTCTGTGAACGAAACTCTGGTGGTGAACCCTGGGG

DNA

GTCCCATGGGCCTGGCCCACTGCCCCTGGGTGCTCTGGCCCAGGGTGGCACCCTCAGC
SeqlleriCe ATCCCTTCAGTGCAGGCCCGGGACTCTGGCTACTACAACTGCACAGCCACCAACAATG

TGGGCAACCCTGCCAAGAAGACTGTCAACCTGCTGGTGCGATCCATGAAGAACGCTAC

ATTCCAGATCACTCCTGACGTGATCAAAGAGAGTGAGAACATCCAGCTGGGCCAGGAC

CTGAAGCTATCGTGCCACGTGGATGCAGTGCCCCAGGAGAAGGTGACCTACCAGTGGT

TCAAGAATGGCAAGCCGGCACGCATGTCCAAGCGGCTGCTGGTGACCCGCAATGATCC

TGAGCTGCCCGCAGTCACCAGCAGCCTAGAGCTCATTGACCTGCACTTCAGTGACTAT

GGCACCTACCTGTGCATGGCTTCTTTCCCAGGGGCACCCGTGCCCGACCTCAGCGTCG

AGGTCAACATCTCCTCTGAGACAGTGCCGCCCACCATCAGTGTGCCCAAGGGTAGGGC

CGTGGTGACCGTGCGCGAGGGATCGCCTGCCGAGCTGCAATGCGAGGTGCGGGGCAAG

CCGCGGCCGCCAGTGCCCTGGTCCCGCGTGGACAAGGAGGCTGCACTGCTGCCCTCGG

GGCTGCCCCTGGAGGAGACTCCGGACGGGAAGCTACGGCTGGAGCGAGTGAGCCGAGA

CATGAGCGGGACCTACCGCTGCCAGACGGCCCGCTATAATGGCTTCAACGTGCGCCCC

CGTGAGGCCCAGGTGCAGCTGAACGTGCAGGAATTC

ORF Start: GGT ORF Stop:
at 1 SEQ ID NO: 40 302 as MW at 32832.1kD

NOVI2b, GTPPALKLSVNETLVVNPGENVTVQCLLTGGDPLPQLQWSHGPGPLPLGALAQGGTLS

l7OlOH372 IPSVQ'~ARDSGYYNCTATNNVGNPAKKTVNLLVRSMKNATFQITPDVIKESENIQLGQD

PrOtelri LKLSCHVDAVPQEKVTYQWFKNGKPARMSKRLLVTRNDPELPAVTSSLELIDLHFSDY
S8C1l1eriCe GTYLCMASFPGAPVPDLSVEVNISSETVPPTISVPKGRAVVTVREGSPAELQCEVRGK

PRPPVPWSRVDKEAALLPSGLPLEETPDGKLRLERVSRDMSGTYRCQTARYNGFNVRP

REAQVQLNVQEF

SEQ ID NO: 41 906 by NOV12C, GGTACCCCACCAGCCCTGAAGCTGTCTGTGAACGAAACTCTGGTGGTGAACCCTGGGG

DNA

GTCCCATGGGCCTGGCCCACTGCCCCTGGGTGCTCTGGCCCAGGGTGGCACCCTCAGC
S2C1t12riCe ATCCCTTCAGTGCAGGCCCGGGACTCTGGCTACTACAACTGCACAGCCACCAACAATG

TGGGCAACCCTGCCAAGAAGACTGTCAACCTGCTGGTGCGATCCATGAAGAACGCTAC

ATTCCAGATCACTCCTGACGTGATCAAAGAGAGTGAGAACATCCAGCTGGGCCAGGAC

CTGAAGCTATCGTGCCACGTGGATGCAGTGCCCCAGGAGAAGGTGACCTACCAGTGGT

TCAAGAATGGCAAGCCGGCACGCATGTCCAAGCGGCTGCTGGTGACCCGCAATGATCC

TGAGCTGCCCGCAGTCACCAGCAGCCTAGAGCTCATTGACCTGCACTTCAGTGACTAT

GGCACCTACCTGTGCATGGCTTCTTTCCCAGGGGCACCCGTGCCCGACCTCAGCGTCG

AGGTCAACATCTCCTCTGAGACAGTGCCGCCCACCATCAGTGTGCCCAAGGGTAGGGC

CGTGGTGACCGTGCGCGAGGGATCGCCTGCCGAGCTGCAATGCGAGGTGCGGGGCAAG

CCGCGGCCGCCAGTGCTCTGGTCCCGCGTGGACAAGGAGGCTGCACTGCTGCCCTCGG

GGCTGCCCCTGGAGGAGACTCCGGACGGGAAGCTGCGGCTGGAGCGAGTGAGCCGAGA

CATGAGCGGGACCTACCGCTGCCAGACGGCCCGCTATAATGGCTTCAACGTGCGCCCC

CGTGAGGCCCAGGTGCAGCTGAACGTGCAGGAATTC

ORF Start: GGT ORF Stop:
at 1 SEQ ID NO: 42 302 as MW at 32848.2kD

NOV12C, GTPPALKLSVNETLVVNPGENVTVQCLLTGGDPLPQLQWSHGPGPLPLGALAQGGTLS

l7O1O8393 IPSVQ'~RDSGYYNCTATNNVGNPAKKTVNLLVRSMKNATFQITPDVIKESENIQLGQD

PIOtelri S8C1L1eriCe L~SCHVDAVPQEKVTYQWFKNGKPARMSKRLLVTRNDPELPAVTSSLELIDLHFSDY

GTYLCMASFPGAPVPDLSVEVNISSETVPPTISVPKGRAVVTVREGSPAELQCEVRGK

PRPPVLWSRVDKEAALLPSGLPLEETPDGKLRLERVSRDMSGTYRCQTARYNGFNVRP

I REAQVQLNVQEF

SEQ ID NO: 43 720 by .
NOV12C1, GGTACCTTGAACCAGCACAATGCGGTGGTCAAGGCCATCCCGGTCCGGCGTGTGGAGA

DNA

CCGCCTCACACCCTATACCACCTTCGGGGCTGGTGACATGGCCTCCCGCATCATCCAC
SeqileriCe TACACAGAGCCCATCAACTCTCCGAACCCTTCAGACAACACCTGCCACTTTGAGGATG

AGAAGATCTGTGGCTATACCCAGGACCTGACAGACAACTTTGACTGGACGCGGCAGAA

TGCCCTCACCCAGAACCCCAAACGCTCCCCCAACACTGGTCCCCCCACCGACATAAGT

GGCACCCCTGAGGGCTACTACATGTTCATCGAGACATCGAGGCCTCGGGAGCTGGGGG

ACCGTGCAAGGTTAGTGAGTCCCCTCTACAATGCCAGCGCCAAGTTCTACTGTGTCTC

CTTCTTCTACCACATGTACGGGAAACACATCGGCTCCCTCAACCTCCTGGTGCGGTCC

CGGAACAAAGGGGCTCTGGACACGCACGCCTGGTCTCTCAGTGGCAATAAGGGCAATG

TGTGGCAGCAGGCCCATGTGCCCATCAGCCCCAGTGGGCCCTTCCAGATTATTTTTGA

GGGGGTTCGAGGCCCGGGCTACCTGGGGGATATTGCCATAGATGACGTCACACTGAAG

AAGGGGGAGTGTCCCCGGGAATTC

ORF Start: GGT ORF Stop:
at 1 at 721 SEQ ID NO: 44 240 as MW at 26966.1kD

NOV12C1, GTLNQHNAWKAIPVRRVEKGQLLEYILTDLRVPHSYEVRLTPYTTFGAGDMASRIIH

P1'Otelri S2C1L1CriCe GTPEGYYMFIETSRPRELGDRARLVSPLYNASAKFYCVSFFYHMYGKHIGSLNLLVRS

RNKGALDTHAWSLSGNKGNVWQQAHVPISPSGPFQIIFEGVRGPGYLGDIAIDDVTLK

KGECPREF

SEQ ID NO: 45 720 by NOVl2e, GGTACCTTGAACCAGCACAATGCGGTGGTCAAGGCCATCCCGGTCCGGCGTGTGGAGA

DNA

CCGCCTCACACCCTATACCACCTTCGGGGCTGGTGACATGGCCTCCCGCATCATCCAC
SeClLleriCe TACACAGAGCCCATCAACTCTCCGAACCTTTCAGACAACACCTGCCACTTTGAGGATG

AGAAGATCTGTGGCTATACCCAGGACCTGACAGACAACTTTGACTGGACGCGGCAGAA

TGCCCTCACCCAGAACCCCAAACGCTCCCCCAACACTGGTCCCCCCACCGACATAAGT

GGCACCCCTGAGGGCTACTACATGTTCATCGAGACATCGAGGCCTCGGGAGCTGGGGG

ACCGTGCAAGGTTAGTGAGTCCCCTCTACAATGCCTGCGCCAAGTTCTACTGTGTCTC

CTTCTTCTACCACATGTACGGGAAACACATCGGCTCCCTCAACCTCCTGGTGCGGTCC

CGGAACAAAGGGGCTCTGGACACGCACGCCTGGTCTCTCAGTGGCAATAAGGGCAATG

TGTGGCAGCAGGCCCATGTGCCCATCAGCCCCAGTGGGCCCTTCCAGATTATTTTTGA

GGGGGTTCGAGGCCCGGGCTACCTGGGGGATATTGCCATAGATGACGTCACACTGAAG

AAGGGGGAGTGTCCCCGGGAATTC

ORF Start: GGT ORF Stop:
at 1 at 721 SEQ ID NO: 46 240 as MW at 26998.2kD

NOVl2e, GTLNQHNAWKAIPVRRVEKGQLLEYILTDLRVPHSYEVRLTPYTTFGAGDMASRIIH

PrOtelri Se i12riC8 GTPEGYYMFIETSRPRELGDRARLVSPLYNACAKFYCVSFFYHMYGKHIGSLNLLVRS

RNKGALDTHAWSLSGNKGNVWQQAHVPISPSGPFQIIFEGVRGPGYLGDIAIDDVTLK

KGECPREF

SEQ ID NO: 47 720 by NOVl2f, GGTACCTTGAACCAGCACAATGCGGTGGTCAAGGCCATCCCGGTCCGGCGTGTGGAGA

DNA

CCGCCTCACACCCTATACCACCTTCGGGGCTGGTGACATGGCCTCCCGCATCATCCAC
SeClLleriCe TACACAGAGCCCATCAACTCTCCGAACCTTTCAGACAACACCTGCCACTTTGAGGATG

AGAAGATCTGTGGCTATACCCAGGACCTGACAGACAACTTTGACTGGACGCGGCAGAA

TGCCCTCACCCAGAACCCCAAACGCTCCCCCAACACTGGTCCCCCCACCGACATAAGT

GGCACCCCTGAGGGCTACTACATGTTCATCGAGACATCGAGGCCTCGGGAGCTGGGGG

ACCGTGCAAGGTTAGTGAGTCCCCTCTACAATGCCAGCGCCAAGTTCTACCGTGTCTC

CTTCTTCTACCACATGTACGGGAAACACATCGGCTCCCTCAACCTCCTGGTGCGGTCC

CGGAACAAAGGGGCTCTGGACACGCACGCCTGGTCTCTCAGTGGCAATAAGGGCAATG

TGTGGCAGCAGGCCCATGTGCCCATCAGCCCCAGTGGGCCCTTCCAGATTATTTTTGA

GGGGGTTCGAGGCCCGGGCTACCTGGGGGATATTGCCATAGATGACGTCACACTGAAG

AAGGGGGAGTGTCCCCGGGAATTC

OItF Start: GGT at 1 012F Stop:
at 721 SEQ ID NO: 48 240 as MW at 2703S.1kD

NOVl2f, GTLNQHNAWKAIPVRRVEKGQLLEYILTDLRVPHSYEVRLTPYTTFGAGDMASRIIH

170684238 PIOtelri YTEPINSPNLSDNTCHFEDEKICGYTQDLTDNFDWTRQNALTQNPKRSPNTGPPTDIS

Se uenCe GTPEGYYMFIETSRPRELGDRARLVSPLYNASAKFYRVSFFYHMYGKHIGSLNLLVRS
q RNKGALDTHAWSLSGNKGNVWQQAHVPISPSGPFQIIFEGVRGPGYLGDIAIDDWLK

KGECPREF

SEQ ID NO: 49 496 by NOVl2g, _GGGTACCTGTGGCTATACCCAGGACCTGACAGACAACTTTGACTGGACGCGGCAGAAT

GCACCCCTGAGGGCTACTACATGTTCATCGAGACATCGAGGCCTCGGGAGCTGGGGGA
SequeriCe CCGTGCAAGGTTAGTGAGTCCCCTCTACAATGCCAGCGCCAAGTTCTACTGTGTCTCC

TTCTTCTATCACATGTACGGGAAACACATCGGCTCCCTCAACCTCCTGGTGCGGTCCC

GGAACAAAGGGGCTCTGGACACGCACGCCTGGTCTCTCAGTGGCAATAAGGGCAATGT

GTGGCAGCAGGCCCATGTGCCCATCAGTCCCAGTGGGCCCTTCCAGATTATTTTTGAG

GGGGTTCGAGGCCCGGGCTACCTGGGGGATATTGCCATAGATGACGTCACACTGAAGA

AGGGGGAGTGTCCCCGGAAGCAGACGGAATTC

ORF Start: GGT at 2 ORF Stop:
at 497 SEQ ID NO: SO 165 as MW at 18420.S1cD

NOVl2g, GTCGYTQDLTDNFDWTRQNALTQNPKRSPNTGPPTDISGTPEGYYMFIETSRPRELGD

17O534177 PIOtelri ~I'VSPLYNASAKFYCVSFFYHMYGKHIGSLNLLVRSRNKGALDTHAWSLSGNKGNV

SequeriCe Z''1QQ~VPISPSGPFQIIFEGVRGPGYLGDIAIDDVTLKKGECPRKQTEF

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 12B.
Table 12B.
Comparison of NOVl2a against NOVl2b through NOVl2g.

Protein SequenceNOVl2a Residues/Identities/

Match ResiduesSimilarities for the Matched Region NOV 12b 239..536 283/298 (94%) 3..300 283/298 (94%) NOV 12c 239..536 284/298 (9S%) 3..300 284/298 (9S%) NOV 12d 683..959 234/277 (84%) 3..239 235/277 (84%) NOV 12e 683..959 234/277 (84%) 3..239 235/277 (84%) NOV 12f 683..959 234/277 (84%) 3..239 235/277 (84%) NOVl2g 801..962 161/162 (99%) 3..164 162/162 (99%) Further analysis of the NOV 12a protein yielded the following properties shown in Table 12C.

Table 12C. Protein Sequence Properties NOVl2a PSort 0.3700 probability located in outside; 0.1900 probability located in lysosome analysis:(lumen); 0.1000 probability located in endoplasmic reticulum (membrane);

0.1000 probability located in endoplasmic reticulum (lumen) SignalPLikely cleavage site between residues 19 and 20 analysis:

A search of the NOV 12a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 12D.
Table 12D. Geneseq Results for NOVl2a NOVl2a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value ResiduesRegion AAE00582Human nuclear cell adhesion23..959 487/946 (51%)0.0 molecule 1 protein - 15..912 656/946 (68%) homologue, NCAM_d _ Homo Sapiens, 946 as [W020012921 S-A2, 26-APR-2001 ]

AAE00581Human cell adhesion molecule23..959 487/946 (51%)0.0 homologue (CAM-H) protein 15..912 656/946 (68%) #1 -Homo sapiens, 1018 aa.

[W0200129215-A2, 26-APR-2001]

AAE00586Human nuclear cell adhesion71..959 455/898 (50%)0.0 molecule homologue, NCAM_d 8..857 617/898 (68%) 2 protein -_ Homo sapiens, 891 as [W0200129215-A2, 26-APR-2001 ]

AAY72717HBXDJ03 clone human attractin-like508..965416/458 (90%)0.0 protein #2 - Homo Sapiens,1..418 417/458 (90%) 448 aa.

[W0200116156-A1, 08-MAR-2001]

AAY72714HBXDJ03 clone human attractin-like508..965406/458 (88%)0.0 protein #1 - Homo Sapiens,1..418 407/458 (88%) 448 aa.

[W0200116156-A1, 08-MAR-2001]

In a BLAST search of public sequence databases, the NOV 12a protein was found to have homology to the proteins shown in the BLASTP data in Table 12E.
Table 12E. Public BLASTP Results for NOVl2a NOVl2a Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched Value Number Residues Portion CAB86654 DJ402N21.3 (NOVEL PROTEIN239..536 298/299 (99%)e-172 WITH IMMUNOGLOBUL1N 1..299 298/299 (99%) DOMAINS) - Homo Sapiens (Human), 299 as (fragment).

CAB86653 DJ402N21.2 (NOVEL PROTEIN683..965 242/283 (85%)e-138 WITH MAM DOMAIN) - Homo 1..243 242/283 (85%) Sapiens (Human), 273 as (fragment).

Q9DBX0 1200011I03RIK PROTEIN 689..965 227/277 (81%)e-129 - Mus musculus (Mouse), 267 1..237 232/277 (82%) aa.

Q9GMT4 HYPOTHETICAL 51.2 KDA 508..959 205/461 (44%)e-109 PROTEIN - Macaca fascicularis1..414 281/461 (60%) (Crab eating macaque) (Cynomolgus monkey), 448 aa.

CAB86655 DJ402N21.1 (NOVEL PROTEIN)1..127 127/127 (100%)3e-68 -Homo Sapiens (Human), 1..127 127/127 (100%) 127 as (fragment).

PFam analysis predicts that the NOV 12a protein contains the domains shown in the Table 12F.
Table 12F. Domain Analysis of NOVl2a Identities/

Pfam Domain NOVl2a Match RegionSimilarities Expect Value for the Matched Region ig: domain 53..110 14/61 (23%) 2.5e-08 1 of 7 42/61 (69%) ig: domain 150..216 14/70 (20%) 3.7e-09 2 of 7 51/70 (73%) ig: domain 255..310 18/58 (31%) 2.4e-08 3 of 7 38/58 (66%) PKD: domain 239..327 22/100 (22%) 7.3 1 of 1 56/100 (56%) ig: domain 350..417 15/69 (22%) 6.3e-11 4 of 7 49/69 (71 %) ig: domain 456..516 18/64 (28%) 1.7e-08 of 7 46/64 (72%) ig: domain 553..617 16/66 (24%) 0.00011 6 of 7 39/66 (59%) fn3: domain 643..733 20/93 (22%) 0.98 1 of 1 53/93 (57%) ig: domain 801..875 7/78 (9%) 37 7 of 7 54/78 (69%) MAM: domain 1 of 1 793..958 65/180 (36%) 1.3e-52 132/180 (73%) FXAMP1,R 1 ~_ The NOV13 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 13A.
Table 13A. NOV13 Sequence Analysis SEQ ID NO: 51 14169 by NOVl3a, TCTTCGTCGCCGCTCTCTCTCTCACCTCTCAGGGAAAGGGGGGGACATAGGGGCGTCG

DNA

GAAGCACCGGCCGTGAAGATGGAGGTGACCTGCCTTCTACTTCTGGCGCTGATCCCCT
Sequence TCCACTGCCGGGGACAAGGAGTCTACGCTCCAGCCCAGGCGCAGATCGTGCATGCGGG

CCAGGCATGTGTGGTGAAAGAGGACAATATCAGCGAGCGTGTCTACACCATCCGGGAG

GGGGACACCCTCATGCTGCAGTGCCTTGTAACAGGGCACCCTCGACCCCAGGTACGGT

GGACCAAGACGGCAGGTAGCGCCTCGGACAAGTTCCAGGAGACATCGGTGTTCAACGA

GACGCTGCGCATCGAGCGTATTGCACGCACGCAGGGCGGCCGCTACTACTGCAAGGCT

GAGAACGGCGTGGGGGTGCCGGCCATCAAGTCCATCCGCGTGGACGTGCAGTACCTGG

ATGAGCCAATGCTGACGGTGCACCAGACGGTGAGCGATGTGCGAGGCAACTTCTACCA

GGAGAAGACGGTGTTCCTGCGCTGTACTGTCAACTCCAACCCGCCTGCCCGCTTCATC

TGGAAGCGGGGTTCCGATACCCTATCCCACAGCCAGGACAATGGGGTTGACATCTATG

AGCCCCTCTACACTCAGGGGGAGACCAAGGTCCTGAAGCTGAAGAACCTGCGGCCCCA

GGACTATGCCAGCTACACCTGCCAGGTGTCTGTGCGTAACGTGTGCGGCATCCCAGAC

AAGGCCATCACCTTCCGGCTCACCAACACCACGGCACCACCAGCCCTGAAGCTGTCTG

TGAACGAAACTCTGGTGGTGAACCCTGGGGAGAATGTGACGGTGCAGTGTCTGCTGAC

AGGCGGTGATCCCCTCCCCCAGCTGCAGTGGTCCCATGGGCCTGGCCCACTGCCCCTG

GGTGCTCTGGCCCAGGGTGGCACCCTCAGCATCCCTTCAGTGCAGGCCCGGGACTCTG
GCTACTACAACTGCACAGCCACCAACAATGTGGGCAACCCTGCCAAGAAGACTGTCAA
CCTGCTGGTGCGATCCATGAAGAACGCTACATTCCAGATCACTCCTGACGTGATCAAA
GAGAGTGAGAACATCCAGCTGGGCCAGGACCTGAAGCTATCGTGCCACGTGGATGCAG
TGCCCCAGGAGAAGGTGACCTACCAGTGGTTCAAGAATGGCAAGCCGGCACGCATGTC
CAAGCGGCTGCTGGTGACCCGCAATGATCCTGAGCTGCCCGCAGTCACCAGCAGCCTA
GAGCTCATTGACCTGCACTTCAGTGACTATGGCACCTACCTGTGCATGGCTTCTTTCC
CAGGGGCACCCGTGCCCGACCTCAGCGTCGAGGTCAACATCTCCTCTGAGACAGTGCC
GCCCACCATCAGTGTGCCCAAGGGTAGGGCCGTGGTGACCGTGCGCGAGGGATCGCCT
GCCGAGCTGCAATGCGAGGTGCGGGGCAAGCCGCGGCCGCCAGTGCTCTGGTCCCGCG
TGGACAAGGAGGCTGCACTGCTGCCCTCGGGGCTGCCCCTGGAGGAGACTCCGGACGG
GAAGCTGCGGCTGGAGCGAGTGAGCCGAGACATGAGCGGGACCTACCGCTGCCAGACG
GCCCGCTATAATGGCTTCAACGTGCGCCCCCGTGAGGCCCAGGTGCAGCTGAACGTGC
AGTTCCCGCCGGAGGTGGAGCCCAGTTCCCAGGACGTGCGCCAGGCGCTGGGCCGGCC
CGTGCTCCTGCGCTGCTCGCTGCTGCGAGGCAGCCCCCAGCGCATCGCCTCGGCTGTG
CGCCGGATCACGCGGAGCTGCGCCTCGACGCCGTAACTCGCGACAGCAGCGGCAGCTA
CGAGTGCAGCGTCTCCAACGATGTGGGCTCGGCTGCCTGCCTCTTCCAGGTCTCCGCC
AAAGCCTACAGCCCGGAGTTTTACTTCGACACCCCCAACCCCACCCGCAGCCACAAGC
TGTCCAAGAACTACTCCTACGTGCTGCAGTGGACTCAGAGGGAGCCCGACGCTGTCGA
CCCTGTGCTCAACTACAGACTCAGCATCCGCCAGTTGAACCAGCACAATGCGGTGGTC
AAGGCCATCCCGGTCCGGCGTGTGGAGAAGGGGCAGCTGCTGGAGTACATCCTGACCG
ATCTCCGTGTGCCCCACAGCTATGAGGTCCGCCTCACACCCTATACCACCTTCGGGGC
TGGTGACATGGCCTCCCGCATCATCCACTACACAGAGCCCATCAACTCTCCGAACCTT
TCAGACAACACCTGCCACTTTGAGGATGAGAAGATCTGTGGCTATACCCAGGACCTGA
CAGACAACTTTGACTGGACGCGGCAGAATGCCCTCACCCAGAACCCCAAACGCTCCCC
CAACACTGGTCCCCCCACCGACATAAGTGGCACCCCTGAGGGCTACTACATGTTCATC
GAGACATCGAGGCCTCGGGAGCTGGGGGACCGTGCAAGGTTAGTGAGTCCCCTCTACA
ATGCCAGCGCCAAGTTCTACTGTGTCTCCTTCTTCTACCACATGTACGGGAAACACAT
CGGCTCCCTCAACCTCCTGGTGCGGTCCCGGAACAAAGGGGCTCTGGACACGCACGCC
TGGTCTCTCAGTGGCAATAAGGGCAATGTGTGGCAGCAGGCCCATGTGCCCATCAGCC

CCAGTGGGCCCTTCCAGATTATTTTTGAGGGGGTTCGAGGCCCGGGCTACCTGGGGGA

TATTGCCATAGATGACGTCACACTGAAGAAGGGGGAGTGTCCCCGGAAGCAGACGGAT

CCCAATAAAGGTGCAAGACGGGAAGGAGCTGCCTGCGATGGCCTGAAATTCCACCTTT

CATCCCCTATGGATGACGGAGAGCTTACAGATGACCCTATTGAATGCAAGCACCTTTG

GATCCATAGAGTGGACAGTAAAGGTGCTCAGTACATGTTGGCTGAGCTGAACTGCATA

CATGTGGCCCCCAGGTTCCTGGTCTTTATGGACGAAGGGCACAAGGTTGGTGAAAAGG

ACTCCGGGGGCCAGCCCTTCCAAGTTTACACTGATTTCTCCTTTTACCCTCATGCTAT

CCCTGAGAAGATGTCAATAATGCCCACGTTACAGGTGGGAAAACTGAGGCTTAGAGAG

GAGGAGGAATCTGCCTACGGTCACACAGCTGCAAAGGCTAGAGCTGGGACCAGGAGCT

GGTCTCTTAACCGACCACCTGAGCTCAAGAGCTTTTCTCTCTGGACCAACATGACCCA

AAGTGTGCGCGAGCCTATCACAGGTCCCCTGCAATGCCAAACATACACGCACAGCAAT

ACACAACACCTGGGGACATGGATGAAGCTGGAAACCATCATTCTCAGCAAACTGACAC

AAGAACAGAAAACCAAACACCACATGTTCTCACTCACCACCCAGTCTGCCCCGCCCTC

TCTCTTCTCACCTGAACTTCCCCTCTCCTCAAACTCTCGAGGCCACGCCTCTATGTCC

TTGGATGATGATGATGACGACGACGACGATGATGATGATGATGATGACGACGATGACA

ATGATGATGATGATGGAAGGAAGACCTACAGAATCCCTCCAGGCTCTGACCTCAGTGC

TTGTGGGTGGGTGAATGACCACATGTCGCAGGGAGACTCCACAGGTCCTCCCGATGAG

AAGCACTCTTATGCCAAAGAGGAGACTCAGGCCAAACTGACAGGACCAGGAATTAGCT

ACCCTGGTAAACCCAGCTATCGACTGCACCCGAGCGGCTACACACCACTGGAGCAGTT

CAGGGAGAAAGCCACCGGCATGCTCACCCCGTATGTCTCTGGCTCTGTTTCCTCTTTC

TGCTTCCCCTTCCCCACCTCTGAGTCTCTGTGTTCTGCTCATGCCAATTCCCCTTCTG

CCTGTCTCTGCCCGCTTCTCTCTGGGCTGGTCTCTCCGAGACTCTGTTCCCTTGGCTG

GCATGCCCTCCACCTCCCCTGATGGTTCAGCAGAGATGAAGCCGGCCTGGCTCATGGG

TGTGGGTAATGTACTAGTGCAGGAGAGTGGTGGGGCCCAGTCTGGGTGCAG

ORF Start: ATG ORF Stop:
at 13S TGA at SEQ ID NO: S2 131 S MW at 145782.9kD
as NOV 13a, MEW CLLLLALI PFHCRGQGWAPAQAQI
VHAGQACWKEDNI
SERWTIREGDTLML

Protein SeC111eriCe PAIKSIRVDVQYLDEPMLTVHQTVSDVRGNFYQEKTVFLRCTVNSNPPARFIWKRGSD

TLSHSQDNGVDIYEPLYTQGETKVLKLKNLRPQDYASYTCQVSVRNVCGIPDKAITFR

LTNTTAPPALKLSVNETLVVNPGENVTVQCLLTGGDPLPQLQWSHGPGPLPLGALAQG

GTLSIPSVQARDSGYYNCTATNNVGNPAKKTVNLLVRSMKNATFQITPDVIKESENIQ

LGQDLKLSCHVDAVPQEKWYQWFKNGKPARMSKRLLVTRNDPELPAVTSSLELIDLH

FSDYGTYLCMASFPGAPVPDLSVEVNISSETVPPTISVPKGRAVVTVREGSPAELQCE

VRGKPRPPVLWSRVDKEAALLPSGLPLEETPDGKLRLERVSRDMSGTYRCQTARYNGF

NVRPREAQVQLNVQFPPEVEPSSQDVRQALGRPVLLRCSLLRGSPQRIASAVWRFKGQ

LLPPPPWPAAAEAPDHAELRLDAWRDSSGSYECSVSNDVGSAACLFQVSAKAYSPE

FYFDTPNPTRSHKLSKNYSYVLQWTQREPDAVDPVLNYRLSIRQLNQHNAWKAIPVR

RVEKGQLLEYILTDLRVPHSYEVRLTPYTTFGAGDMASRIIHYTEPINSPNLSDNTCH

FEDEKICGYTQDLTDNFDWTRQNALTQNPKRSPNTGPPTDISGTPEGYYMFIETSRPR

ELGDRARLVSPLYNASAKFYCVSFFYHMYGKHIGSLNLLVRSRNKGALDTHAWSLSGN

KGNVWQQAHVPISPSGPFQIIFEGVRGPGYLGDIAIDDVTLKKGECPRKQTDPNKGAR

REGAACDGLKFHLSSPMDDGELTDDPIECKHLWIHRVDSKGAQYMLAELNCIHVAPRF

LVFMDEGHKVGEKDSGGQPFQWTDFSFYPHAIPEKMSIMPTLQVGKLRLREEEESAY

GHTAAKARAGTRSWSLNRPPELKSFSLWTNMTQSVREPITGPLQCQTYTHSNTQHLGT

WMKLETIILSKLTQEQKTKHHMFSLTTQSAPPSLFSPELPLSSNSRGHASMSLDDDDD

DDDDDDDDDDDDDNDDDDGRKTYRIPPGSDLSACGWVNDHMSQGDSTGPPDEKHSYAK

EETQAKLTGPGISYPGKPSYRLHPSGYTPLEQFREKATGMLTPYVSGSVSSFCFPFPT

SESLCSAHANSPSACLCPLLSGLVSPRLCSLGWHALHLP

SEQ ID NO: S3 1 S00 by NOVl3b, TGAGCCGAGACATGAGCGGGACCTACCGCTGCCAGACGGCCCGCTATAATGGCTTCAA

DNA

CCCAGTTCCCAGGACGTGCGCCAGGCGCTGGGCCGGCCCGTGCTCCTGCGCTGCTCGC
SeCllteriC2 TGCTGCGAGGCAGCCCCCAGCGCATCGCCTCGGCTGTGTGGCGTTTCAAAGGGCAGCT

GCTGCCGCCGCCGCCTGTTGTTCCCGCCGCCGCCGAGGCGCCGGATCACGCGGAGCTG

CGCCTCGACGCCGTAACTCGCGACAGCAGCGGCAGCTACGAGTGCAGCGTCTCCAACG

ATGTGGGCTCGGCTGCCTGCCTCTTCCAGGTCTCCGCCAAAGCCTACAGCCCGGAGTT

TTACTTCGACACCCCCAACCCCACCCGCAGCCACAAGCTGTCCAAGAACTACTCCTAC

GTGCTGCAGTGGACTCAGAGGGAGCCCGACGCTGTCGACCCTGTGCTCAACTACAGAC

TCAGCATCCGCCAGTTGAACCAGCACAATGCGGTGGTCAAGGCCATCCCGGTCCGGCG

TGTGGAGAAGGGGCAGCTGCTGGAGTACATCCTGACCGATCTCCGTGTGCCCCACAGC

TATGAGGTCCGCCTCACACCCTATACCACCTTCGGGGCTGGTGACATGGCCTCCCGCA

TCATCCACTACACAGAGCGCCAGATCCGCTGGCCCCCAGTCCTGGCTCTGAGGACCCT

GTCCTCTGGTCCCAAGCAGGGTATCCTCTGCAGAGCCCCACACCTCAGTTCTGACTTG

GTTTCCCCGCTTGCTTTCTCAGCCATCAACTCTCCGAACCTTTCAGACAACACCTGCC

ACTTTGAGGATGAGAAGATCTGTGGCTATACCCAGGACCTGACAGACAACTTTGACTG

GACGCGGCAGAATGCCCTCACCCAGAACCCCAAACGCTCCCCCAACACTGGTCCCCCC

ACCGACATAAGTGGCACCCCTGAGGGCTACTACATGTTCATCGAGACATCGAGGCCTC

GGGAGCTGGGGGACCGTGCAAGGTTAGTGAGTCCCCTCTACAATGCCAGCGCCAAGTT

CTACTGTGTCTCCTTCTTCTACCACATGTACGGGAAACACATCGGCTCCCTCAACCCC

CTGGTGCGGTCCCGGAACAAAGGGGCTCTGGACACGCACGCCTGGTCTCTCAGTGGCA

ATAAGGGCAATGTGTGGCAGCAGGCCCATGTGCCCATCAGCCCCAGTGGGCCCTTCCA

GATTATTTTTGAGGGGGTTCGAGGCCCGGGCTACCTGGGGGATATTGCCATAGATGAC

GTCACACTGAAGAAGGGGGAGTGTCCCCGGAAGCAGACGGATCCCAATAAAGTGGTGG

TGATGCCGGGCAGTGGAGCCCCCTGCCAGTCCAGCCCACAGCTGTGGGGGCCCATGGC

CATCTTCCTCTTGGCGTTGCAGAGATGATGAGAGCTGTGTGGCCACCCCC

ORF Start: ATG ORF Stop:
at 12 TGA at SEQ ID NO: S4 488 as MW at 54357.1kD

NOVl3b, MSGTYRCQTARYNGFNVRPREAQVQLNVQFPPEVEPSSQDVRQALGRPVLLRCSLLRG

PrOtelri SeCllleriCe ~CLFQVSAKAYSPEFYFDTPNPTRSHKLSKNYSYVLQWTQREPDAVDPVLNYRLSIR

QLNQHNAWKAIPVRRVEKGQLLEYILTDLRVPHSYEVRLTPYTTFGAGDMASRIIHY

TERQIRWPPVLALRTLSSGPKQGILCRAPHLSSDLVSPLAFSAINSPNLSDNTCHFED

EKICGYTQDLTDNFDWTRQNALTQNPKRSPNTGPPTDISGTPEGYYMFIETSRPRELG

DRARLVSPLYNASAKFYCVSFFYHMYGKHIGSLNPLVRSRNKGALDTHAWSLSGNKGN

VWQQAHVPISPSGPFQIIFEGVRGPGYLGDIAIDDVTLKKGECPRKQTDPNKVVVMPG

SGAPCQSSPQLWGPMAIFLLALQR

SEQ ID NO: SS 1828 by NOV13C, TGAGCCGAGACATGAGCGGGACCTACCGCTGCCAGACGGCCCGCTATAATGGCTTCAA

DNA

CCCAGTTCCCAGGACGTGCGCCAGGCGCTGGGCCGGCCCGTGCTCCTGCGCTGCTCGC
SeChleriCB

TGCTGCGAGGCAGCCCCCAGCGCATCGCCTCGGCTGTGTGGCGTTTCAAAGGGCAGCT

GCTGCCGCCGCCGCCTGTTGTTCCCGCCGCCGCCGAGGCGCCGGATCACGCGGAGCTG

CGCCTCGACGCCGTAACTCGCGACAGCAGCGGCAGCTACGAGTGCAGCGTCTCCAACG

ATGTGGGCTCGGCTGCCTGCCTCTTCCAGGTCTCCGCCAAAGCCTACAGCCCGGAGTT

TTACTTCGACACCCCCAACCCCACCCGCAGCCACAAGCTGTCCAAGAACTACTCCTAC

GTGCTGCAGTGGACTCAGAGGGAGCCCGACGCTGTCGACCCTGTGCTCAACTACAGAC

TCAGCATCCGCCAGTTGAACCAGCACAATGCGGTGGTCAAGGCCATCCCGGTCCGGCG

TGTGGAGAAGGGGCAGCTGCTGGAGTACATCCTGACCGATCTCCGTGTGCCCCACAGC

TATGAGGTCCGCCTCACACCCTATACCACCTTCGGGGCTGGTGACATGGCCTCCCGCA

TCATCCACTACACAGAGCGCCAGATCCGCTGGCCCCCAGTCCTGGCTCTGAGGACCCT

GTCCTCTGGTCCCAAGCAGGGTATCCTCTGCAGAGCCCCACACCTCAGTTCTGACTTG

GTTTCCCCGCTTGCTTTCTCAGCCATCAACTCTCCGAACCTTTCAGACAACACCTGCC

ACTTTGAGGATGAGAAGATCTGTGGCTATACCCAGGACCTGACAGACAACTTTGACTG

GACGCGGCAGAATGCCCTCACCCAGAACCCCAAACGCTCCCCCAACACTGGTCCCCCC

ACCGACATAAGTGGCACCCCTGAGGGCTACTACATGTTCATCGAGACATCGAGGCCTC

GGGAGCTGGGGGACCGTGCAAGGTTAGTGAGTCCCCTCTACAATGCCAGCGCCAAGTT

CTACTGTGTCTCCTTCTTCTACCACATGTACGGGAAACACATCGGCTCCCTCAACCCC

CTGGTGCGGTCCCGGAACAAAGGGGCTCTGGACACGCACGCCTGGTCTCTCAGTGGCA

ATAAGGGCAATGTGTGGCAGCAGGCCCATGTGCCCATCAGCCCCAGTGGGCCCTTCCA

GATTATTTTTGAGGGGGTTCGAGGCCCGGGCTACCTGGGGGATATTGCCATAGATGAC

GTCACACTGAAGAAGGGGGAGTGTCCCCGGAAGCAGACGGATCCCAATAAAGGTGCAA

GACGGGAAGGAGGTGGGGGAGCTGAATCTGGAGGGAGCTGTGCGTGGCGGGGGTTCCT

GTCTGTTGAGGGAGGGTGTTCGGGTCTGAATAGGGGTTCAGACTGTCTGATGATGGGA

ATCAGGTGGCTCTGACTGTGTTAACGTGTGCCCACAACTCACGTCAGGCTGAGAACTG

GTGTAACACCATGAGAAAGCTTGGCCCCCACCATCGTGATGAGCATACCGACCTGGTC

ACCGGAACACAAACACCAACAACCACAGAGGGCGCCTCAGAATACCCAGAGGGCCCAA

TACGCCGACCCGCTGTCACGAGCGCCCACGAGCGGCAGAACACGACAGGCACACAACC

AGCCGGAGCAAGACGGAGCCGAGAGCCCCGGGGACATAGACCCCAGCAAGCGACACAC

AAGGACGCGCACAGAGCGCACACACTAACA

OItF Start: ATG ORF Stop:
at 12 TGA at SEQ ID NO: 56 503 as MW at 55764.4kD

NOV13C, MSGTYRCQTARYNGFNVRPREAQVQLNVQFPPEVEPSSQDVRQALGRPVLLRCSLLRG

PrOteln SequeriCe ~CLFQVSAKAYSPEFYFDTPNPTRSHKLSKNYSYVLQWTQREPDAVDPVLNYRLSIR

QLNQHNAWKAIPVRRVEKGQLLEYILTDLRVPHSYEVRLTPYTTFGAGDMASRIIHY

TERQIRWPPVLALRTLSSGPKQGILCRAPHLSSDLVSPLAFSAINSPNLSDNTCHFED

EKICGYTQDLTDNFDWTRQNALTQNPKRSPNTGPPTDISGTPEGYYMFIETSRPRELG

DRARLVSPLYNASAKFYCVSFFYHMYGKHIGSLNPLVRSRNKGALDTHAWSLSGNKGN

VWQQAHVPISPSGPFQIIFEGVRGPGYLGDIAIDDVTLKKGECPRKQTDPNKGARREG

GGGAESGGSCAWRGFLSVEGGCSGLNRGSDCLMMGIRWL

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 13B.
Table 13B. Comparison of NOVl3a against NOVl3b through NOVl3c.
Protein Sequence NOVl3a Residues/ Identities/
Match Residues Similarities for the Matched Region NOVl3b 508..925 403/458 (87%) 1..458 403/458 (87%) NOVl3c 508..925 403/458 (87%) 1..458 403/458 (87%) Further analysis of the NOVl3a protein yielded the following properties shown in Table 13C.
Table 13C. Protein Sequence Properties NOVl3a PSort 0.3700 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1000 probability located in endoplasmic reticulum (membrane);
0.1000 probability located in endoplasmic reticulum (lumen) SignalP ~ Likely cleavage site between residues 19 and 20 analysis:
A search of the NOVl3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 13D.
Table 13D. Geneseq Results for NOVl3a NOVl3a Identities/
Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region AAE00582Human nuclear cell adhesion23..919488/906 (53%)0.0 molecule homologue, NCAM_d_115..912657/906 (71%) protein - Homo Sapiens, 946 aa.

[W0200129215-A2, 26-APR-2001]

AAE00581Human cell adhesion molecule23..919488/906 (53%)0.0 homologue (CAM-H) protein 15..912657/906 (71%) #1 -Homo Sapiens, 1018 aa.

[W0200129215-A2, 26-APR-2001 ]

AAE00586Human nuclear cell adhesion71..919456/858 (53%)0.0 molecule homologue, NCAM_d_28..857 618/858 (71%) protein - Homo Sapiens, 891 aa.

[W0200129215-A2, 26-APR-2001 ]

AAY72717HBXDJ03 clone human attractin-like508..925418/418 (100%)0.0 protein #2 - Homo sapiens,1..418 418/418 (100%) 448 aa.

[W0200116156-Al, 08-MAR-2001]

AAY72714HBXDJ03 clone human attractin-like508..925408/418 (97%)0.0 protein #1 - Homo Sapiens,1..418 408/418 (97%) 448 aa.

[W0200116156-A1, 08-MAR-2001]

In a BLAST search of public sequence databases, the NOV 13a protein was found to have homology to the proteins shown in the BLASTP data in Table 13E.
Table 13E. Public BLASTP Results for NOVl3a NOVl3a Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched Value Number ResiduesPortion CAB86654 DJ402N21.3 (NOVEL PROTEIN239..536298/299 (99%)e-172 WITH IMMUNOGLOBUL1N 1..299 298/299 (99%) DOMAINS) - Homo Sapiens (Human), 299 as (fragment).

CAB86653 DJ402N21.2 (NOVEL PROTEIN683..925243/243 (100%)e-145 WITH MAM DOMAIN) - Homo 1..243 243/243 (100%) Sapiens (Human), 273 as (fragment).

Q9DBX0 1200011I03RIK PROTEIN 689..925228/237 (96%)e-136 - Mus musculus (Mouse), 267 1..237 233/237 (98%) aa.

Q9GMT4 HYPOTHETICAL 51.2 KDA 508..919206/421 (48%)e-115 PROTEIN - Macaca fascicularis1..414 282/421 (66%) (Crab eating macaque) (Cynomolgus monkey), 448 aa.

CAB86655 DJ402N21.1 (NOVEL PROTEIN)1..127 127/127 (100%)3e-68 -Homo Sapiens (Human), 1..127 127/127 (100%) 127 as (fragment).

PFam analysis predicts that the NOV 13a protein contains the domains shown in the Table 13F.
Table 13F. Domain Analysis of NOVl3a Identities/

Pfam Domain NOVl3a Match RegionSimilarities Expect Value for the Matched Region ig: domain 53..110 14/61 (23%) 2.5e-08 1 of 7 42/61 (69%) ig: domain 150..216 14/70 (20%) 3.7e-09 2 of 7 51/70 (73%) ig: domain 255..310 18/58 (31 %) 2.4e-08 3 of 7 38/58 (b6%) PKD: domain 239..327 22/100 (22%) 7.3 1 of 1 56/100 (56%) ig: domain 350..417 15/69 (22%) 6.3e-11 4 of 7 49/69 (71 %) ig: domain 456..516 18/64 (28%) 1.7e-08 of 7 46/64 (72%) ig: domain 553..617 16/66 (24%) 0.00011 6 of 7 39/66 (59%) fn3: domain 643..733 20/93 (22%) 0.98 1 of 1 53/93 (57%) ig: domain 761..835 7/78 (9%) 37 7 of 7 54/78 (69%) MAM: domain 753..918 65/180 (36%) 1.3e-52 1 of 1 132/180 (73%) EXAMPLE 14.
The NOV 14 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 14A.
Table 14A. NOV14 Sequence Analysis SEQ ID NO: 57 330 by NOVl4a, ~GGAGTGGTCAGTTCTGCTGCCGACACGCCCACCCAGCTCGAGATGGCCATGGACACCA

GGGGGAACTGAAACTGCTCCTGCAGCGAGAGCTCACGGAATTCCTCTCGTGCCAAAAG
SequeriCe GAAACCCAGTTGGTTGATAAGATAGTGCAGGACCTGGATGCCAATAAGGACAACGAAG
TGGATTTTAATGAATTCGTGGTCATGGTGGCAGCTCTGACAGTTGCTTGTAATGATTA
CTTTGTAGAACAATTGAAGAAGAAAGGAAAATAAAGGTAA
ORF Start: ATG at 43 ORF Stop: TAA at 322 SEQ ID NO: 58 93 as MW at 10861.61cD

NOVl4a, MAMDTMIRIFHRYSGKARKRFKLSKGELKLLLQRELTEFLSCQKETQLVDKIVQDLDA
CGS9262-O1 PTOtelri N~NEVDFNEFVVMVAALTVACNDYFVEQLKKKGK
Sequence Further analysis of the NOV 14a protein yielded the following properties shown in Table 14B.
Table 14B. Protein Sequence Properties NOVl4a PSort 0.7000 probability located in plasma membrane; O.S337 probability located in analysis: mitochondria) inner membrane; 0.3627 probability located in mitochondria) intermembrane space; 0.2997 probability located in mitochondria) matrix space SignalP No Known Signal Sequence Predicted analysis:
A search of the NOVl4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 14C.
Table 14C. Geneseq Results for NOVl4a NOVl4a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, IdentifierDate] Match for the Value Residues Matched Region AAM402S8 Human polypeptide SEQ ID 2..86 SO/8S (S8%)3e-23 Homo Sapiens, 94 aa. [W0200153312-8..92 66/85 (76%) A 1, 26-JLJL-2001 ]

AAB4SS31 Human S100A1 protein - 2..86 SO/8S (S8%)3e-23 Homo sapiens, 94 aa. [DE1991S48S-A1,8..92 66/85 (76%) OCT-2000]

ABB 12007Human Ca-binding protein 2..84 43/83 (S 3e-18 S 100P 1 %) homologue, SEQ ID N0:2377 25..107 59/83 (70%) - Homo sapiens, 113 aa. [W0200157188-A2, 09-AUG-2001 ]

AAB4SS4S Human S100P protein - Homo2..84 43/83 (S 3e-18 Sapiens, 1%) 9S aa. [DE1991S48S-A1, 7..89 59/83 (70%) 2000]

AAB4SS44 Human S100B protein - Homo2..84 43/83 (S1%)3e-18 Sapiens, 9S aa. [DE1991S48S-A1, 7..89 59/83 (70%) 2000]

In a BLAST search of public sequence databases, the NOV 14a protein was found to have homology to the proteins shown in the BLASTP data in Table 14D.

Table 14D. Public BLASTP
Results for NOVl4a NOVl4a Identities/

Protein Residues/SimilaritiesExpect for Accession Protein/Organism/LengthMatch the Matched Value Number Residues Portion AAL30893 S100Z PROTEIN - Homo 1..93 93/93 (100%)4e-47 sapiens (Human), 99 aa. 7..99 93/93 (100%) S3S98S S-100 protein alpha 2..89 52/88 (S9%) 3e-2S
chain -weatherfish, 9S aa. 7..94 70/88 (79%) P3S467 S-100 protein, alpha 2..86 S2/8S (61%) 4e-23 chain - Rattus norvegicus (Rat), 93 7..91 66/85 (77%) aa.

BCBOIA S-100 protein alpha 2..86 SO/8S (S8%) 1e-22 chain - bovine, 94 aa. 8..92 66/85 (76%) CAC16S47 SEQUENCE 1 FROM PATENT 2..86 SO/8S (S8%) 1e-22 W00061742 - Homo sapiens8..92 66/85 (76%) (Human), 94 aa.

PFam a nalysis predicts that the NOV 14a protein contains the domains shown in the Table 14E.
Table 14E. Domain Analysis of NOVl4a Identities/
Pfam Domain NOVl4a Match Region Similarities Expect Value for the Matched Region 5_100: domain 1 of 1 2..42 20/44 (4S%) 2.8e-09 31/44 (70%) efhand: domain 1 of 1 48..76 6/29 (21 %) 0.0012 25/29 (86%) EXAMPLE 15.
The NOV 1 S clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 1 SA.
Table 15A. NOV15 Sequence Analysis SEQ ID NO: S9 X773 by NOVISa, 'AGCCTTGGGTCGAAGGGATGAGGTGGGGCCTCCTTCAAGAGACAAAGTCTGGTTCTGT

ATCCCTGTGAAGCCCTGCTTCTACCAGAACTTCTCCGACGAGATCCCAGTGGAGCACC
Sequence AGGTCCTGGTGAAGAGGATCTACCGGCTGTGGATGGTTTACTGCGCCACCCTCGGCGT
CAACCTCATTGCCTGCCTGGCCTGGTGGATCGGCGGAGGCTCGGGGACCAACTTCGGC
CTGGCCTTCGTGTGGCTGCTCCTGTTCACGCCTTGCGGCTACGTGTGCTGGTTCCGGC
CTGTCTACAAGGCCTTCCGGGCCGACAGCTCCTTTAATTTCATGGCGTTTTTCTTCAT
CTTCGGAGCCCAGTTTGTCCTGACCGTCATCCAGGCGATTGGCTTCTCCGGCTGGGGC
GCGTGCGGCTGGCTGTCGGCAATTGGATTCTTCCAGTACAGCCCGGGCGCTGCCGTGG
TCATGCTGCTTCCAGCCATCATGTTCTCCGTGTCGGCTGCCATGATGGCCATCGCGAT

CATGAAGGTGCACAGGATCTACCGAGGGGCTGGCGGAAGCTTCCAGAAGGCACAGACG
GAGTGGAACACGGGCACTTGGCGGAACCCACCGTCGAGGGAGGCCCAGTACAACAACT
TCTCAGGCAACAGCCTGCCCGAGTACCCCACTGTGCCCAGCTACCCGGGCAGTGGCCA
GTGGCCTTAGAGGGAGCCT
ORF Start: ATG at 18 ORF Stop:
TAG
at 762 SEQ ID NO: 60 248 as MW at 27780.OkD

NOVISa, MRWGLLQETKSGSVRGFSVPTEKENNFPPLPKFIPVKPCFYQNFSDEIPVEHQVLVKR

CGS863S-O1 PTOtelri IYRLWMVYCATLGVNLIACLAWWIGGGSGTNFGLAFVWLLLFTPCGYVCWFRPVYKAF

SeClLteriCe ~SSFNFMAFFFIFGAQFVLTVIQAIGFSGWGACGWLSAIGFFQYSPGAAVVMLLPA

IMFSVSAAMMAIAIMKVHRIYRGAGGSFQKAQTEWNTGTWRNPPSREAQYNNFSGNSL

PEYPTVPSYPGSGQWP

SEQ ID NO: 61 773 by NOVISb, AGCCTTGGGTTGAAGGGATGAGGTGGGGCCTCCTTCAAGAGACAAAGTCTGGTTCTGT

ATCCCTGTGAAGCCCTGCTTCTACCAGAACTTCTCCGACGAGATCCCAGTGGAGCACC
SeCIU2riC8 AGGTCCTGGTGAAGAGGATCTACCGGCTGTGGATGTTTTACTGCGCCACCCTCGGCGT

CAACCTCATTGCCTGCCTGGCCTGGTGGATCGGCGGAGGCTCGGGGACCAACTTCGGC

CTGGCCTTCGTGTGGCTGCTCCTGTTCACGCCTTGCGGCTACGTGTGCTGGTTCCGGC

CTGTCTACAAGGCCTTCCGAGCCGACAGCTCCTTTAATTTCATGGCGTTTTTCTTCAT

CTTCGGAGCCCAGTTTGTCCTGACCGTCATCCAGGCGATTGGCTTCTCCGGCTGGGGC

GCGTGCGGCTGGCTGTCGGCAATTGGATTCTTCCAGTACAGCCCGGGCGCTGCCGTGG

TCATGCTGCTTCCAGCCATCATGTTCTCCGTGTCGGCTGCCATGATGGCCATCGCGAT

CATGAAGGTGCACAGGATCTACCGAGGGGCTGGCGGAAGCTTCCAGAAGGCACAGACG

GAGTGGAACACGGGCACTTGGCGGAACCCACCGTCGAGGGAGGCCCAGTACAACAACT

TCTCAGGCAACAGCCTGCCCGAGTACCCCACTGTGCCCAGCTACCCGGGCAGTGGCCA

GTGGCCTTAGAGGGAGCCT

ORF Start: ATG at 18 ORF Stop:
TAG
at 762 SEQ ID NO: 62 248 as MW at 27828.1kD

NOVISb, MRWGLLQETKSGSVRGFSVPTEKENNFPPLPKFIPVKPCFYQNFSDEIPVEHQVLVKR

CGS863S-O2 PrOtelri IYRLWMFYCATLGVNLIACLAWWIGGGSGTNFGLAFVWLLLFTPCGYVCWFRPVYKAF

SCClileriCe ~SSFNFMAFFFIFGAQFVLTVIQAIGFSGWGACGWLSAIGFFQYSPGAAVVMLLPA

IMFSVSAAMMAIAIMKVHRIYRGAGGSFQKAQTEWNTGTWRNPPSREAQYNNFSGNSL

PEYPTVPSYPGSGQWP

SEQ ID NO: 63 6S4 by NOV1SC, ATGAGGTGGGGCCTCCTTCAAGAGACAAAGTCTGGTTCTGTCCGTGGGTTCCCGGTCC

CTTCTACCAGAACTTCTCCGACGAGATCCCAGTGGAGCACCAGGTCCTGGTGAAGAGG
SCCllleriCe ATCTACCGGCTGTGGATGTTTTACTGCGCCACCCTCGGCGTCAACCTCATTGCCTGCC

TGGCCTGGTGGATCGGCGGAGGCTCGGGGACCAACTTCGGCCTGGCCTTCGTGTGGCT

GCTCCTGTTCACGCCTTGCGGCTACGTGTGCTGGTTCCGGCCTGTCTACAAGGCCTTC

CGCGGCTGGCTGTCGGCAATTGGATTCTTCCAGTACAGCCCGGGCGCTGCCGTGGTCA

TGCTGCTTCCAGCCATCATGTTCTCCGTGTCGGCTGCCATGATGGCCATCGCGATCAT

GAAGGCGCACAGGATCTACCGAGGGGCTGGCGGAAGCTTCCAGAAGGCACAGACGGAG

TGGAACACGGGCACTTGGCGGAACCCACCGTCGAGGGAGGCCCAGTACAACAACTTCT

CAGGCAACAGCCTGCCCGAGTACCCCACTGTGCCCAGCTACCCGGGCAGTGGCCAGTG

GCCTTAGAGGGAGCCT

ORF Start: ATG at 1 ORF Stop:
TAG
at 643 SEQ ID NO: 64 214 as MW at 24129.8kD

NOVISC, MRWGLLQETKSGSVRGFPVPTEKENNFPPLPKFIPVKPCFYQNFSDEIPVEHQVLVKR
CGS863S-O3 PrOtClri IYRLWMFYCATLGVNLIACLAWWIGGGSGTNFGLAFVWLLLFTPCGYVCWFRPVYKAF
Se lleriCe RGWLSAIGFFQYSPGAAVVMLLPAIMFSVSAAMMAIAIMKAHRIYRGAGGSFQKAQTE
WNTGTWRNPPSREAQYNNFSGNSLPEYPTVPSYPGSGQWP

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 15B.
Table 15B. Comparison of NOVlSa against NOVlSb through NOVlSc.
Protein Sequence NOVlSa Residues/ Identities/
Match Residues Similarities for the Matched Region NOVlSb 1..248 217/248 (87%) 1..248 217/248 (87%) NOVlSc 1..248 191/248 (77%) 1..214 191/248 (77%) Further analysis of the NOV 1 Sa protein yielded the following properties shown in Table 15C.
Table 15C.
Protein Sequence Properties NOVlSa PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis:Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane);

0.0300 probability located in mitochondrial inner membrane SignalP Likely cleavage site between residues 17 and 18 analysis:

A search of the NOV 15a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 15D.
Table 15D. Geneseq Results for NOVlSa NOVlSa Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent for Identifier#, Date] Match the Matched Value Residues Region AAM93439 Human polypeptide, SEQ 21..248 226/228 (99%)e-138 ID NO:

3078 - Homo Sapiens, 2..229 227/228 (99%) 229 aa.

[EP 1130094-A2, OS-SEP-2001 ]

AAM93704 Human polypeptide, SEQ 21..150 127/130 (97%)1e-75 ID NO:

3635 - Homo Sapiens, 2..131 129/130 (98%) 132 aa.

[EP 1130094-A2, OS-SEP-2001 ]

AAM25225 Human protein sequence 21..131 109/111 (98%)1e-64 SEQ ID

N0:740 - Homo Sapiens, 35..145 110/111 (98%) 185 aa.

[W0200153455-A2, 26-JUL-2001]

AAY11904 Human 5' EST secreted 21..126 102/106 (96%)7e-60 protein SEQ

ID No: 504 - Homo Sapiens,2..107 103/106 (96%) 108 aa.

[W09906550-A2, 11-FEB-1999]

AAB62698 Human membrane recycling 23..229 102/208 (49%)Se-56 protein (HMRP)-1 - Homo sapiens, 131..338140/208 (67%) 347 aa.

[US6235715-B1, 22-MAY-2001]

In a BLAST search of public sequence databases, the NOV 1 Sa protein was found to have homology to the proteins shown in the BLASTP data in Table 15E.
Table 15E. Public BLASTP Results for NOVlSa Protein NOVlSa Identities/

AccessionProtein/Organism/Length Residues/SimilaritiesExpect for Number Match the Matched Value Residues Portion Q969E2 HYPOTHETICAL 25.7 KDA 21..248 226/228 (99%)e-138 PROTEIN (SIMILAR TO 2..229 227/228 (99%) SECRETORY CARRIER

MEMBRANE PROTEIN 4) -Homo sapiens (Human), 229 aa.

Q9ET20 SECRETORY CARRIER 23..248 193/227 (85%)e-118 MEMBRANE PROTEIN 4 - Rattus4..230 208/227 (91%) norvegicus (Rat), 230 aa.

Q9JKV5 SECRETORY CARRIER 23..248 190/227 (83%)e-117 MEMBRANE PROTEIN 4 - Mus 4..230 208/227 (90%) musculus (Mouse), 230 aa.

Q9JKE3 SECRETORY CARRIER 22..246 135/232 (58%)2e-81 MEMBRANE PROTEIN 5 - Rattus3..234 167/232 (71%) norvegicus (Rat), 235 aa.

Q9JKD3 SECRETORY CARRIER 22..246 134/232 (57%)7e-81 MEMBRANE PROTEIN 5 - Mus 3..234 166/232 (70%) musculus (Mouse), 235 aa.

PFam analysis predicts that the NOVlSa protein contains the domains shown in the Table 1 SF.
Table 15F. Domain Analysis of NOVlSa Identities/

Pfam Domain NOVlSa Match Similarities Expect Region for the Matched Value Region TspO MBR: domain 63..190 30/164 (18%) 9.5 1 of 1 ( 1/164 9 SS%) chloroa_b-bind: 181..195 5/1 S (33%) 3.7 domain 1 of 1 12/1 S (80%) EXAMPLE 16.
The NOV 16 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 16A.
Table 16A. NOV16 Sequence Analysis SEQ ID NO: 6S 1642 by NOVl6a, GCGGAGTCCGGACGTCGGGAGCAGGATGGCGGCGGAGCAGGACCCCGAGGCGCGCGCG

DNA

CGGGCCGGGCGCGGGACGCCGCCGAGTTCGAGCTCTTCTTCCGCCGCTGCCCGTTCGG
SequeriCe CGGCGCCTTCGCCTTGGTAGCCGGCTTGCGCGACTGTGTGCGCTTCCTGCGCGCCTTC

GACGTGCAGTTCCTGGCCTCGGTGCTGCCCCCAGACACGGATCCTGCGTTCTTCGAGC

ACCTTCGGGCCCTCGACTGCTCCGAGGTGACGGTGCGAGCCCTGCCCGAGGCTCCCTC

GCCTTCCCCGCAGGTGCCGCTCCTGCAGGTGTCCGGGCCGCTCCTGGTGGTGCAGCTG

CTGGAGACACCGCTGCTCTGCCTGGTCAGCTACGCCAGCCTGGTGGCCACCAACGCAG

CGCGCGTTCGCTTGATCGCAGGGCCAGAGAAGCGGCTGCTAGAGATGGGCCTGAGGCG

GGCTCAGGGCCCGATGGGGCCTGACAGCCTCCACCTACAGCTACCTGGGGGCTTCGAC

AGCAGCAGCAACGTGCTAGCGGGCCAGCTGCGAGGTGTGCCGGTGGCCGGGACCCTGG

CCCACTCCTTCGTCACTTCCTTTTCAGGCAGCGAGGTGCCCCCTGACCCGATGTTGGC

GCCAGCAGCTGGTGAGGGCCCTGGGGTGGACCTGGCGGCCAAAGCCCAGGTGTGGCTG

GAGCAGGTGTGTGCCCACCTGGGGCTGGGGGTGCAGGAGCCGCATCCAGGCGAGCGGG

CAGCCTTTGTGGCCTATGCCTTGGCTTTTCCCCGGGCCTTCCAGGGCCTCCTGGACAC

CTACAGCGTGTGGAGGAGTGGTCTCCCCAACTTCCTAGCAGTCGCCTTGGCCCTGGGA

GAGCTGGGCTACCGGGCAGTGGGCGTGAGGCTGGACAGTGGTGACCTGCTACAGCAGG

CTCAGGAGATCCGCAAGGTCTTCCGAGCTGCTGCAGCCCAGTTCCAGGTGCCCTGGCT

GGAGTCAGTCCTCATCGTAGTCAGCAACAACATTGACGAGGAGGCGCTGGCCCGACTG

GCCCAGGAGGGCAGTGAGGTGAATGTCATTGGCATTGGCACCAGTGTGGTCACCTGCC

CCCAACAGCCTTCCCTGGGTGGTGTCTATAAGCTGGTGGCCGTGGGGGGCCAGCCACG

AATGAAGCTGACCGAGGACCCCGAGAAGCAGACGTTGCCTGGGAGCAAGGCTGCTTTC

CGGCTCCTGGGCTCTGACGGGTCTCCACTCATGGACATGCTGCAGTTAGCAGAAGAGC

CAGTGCCACAGGCTGGGCAGGAGCTGAGGGTGTGGCCTCCAGGGGCCCAGGAGCCCTG

CACCGTGAGGCCAGCCCAGGTGGAGCCACTACTGCGGCTCTGCCTCCAGCAGGGACAG

CTGTGTGAGCCGCTCCCATCCCTGGCAGAGTCTAGAGCCTTGGCCCAGCTGTCCCTGA

GCCGACTCAGCCCTGAGCACAGGCGGCTGCGGAGCCCTGCACAGTACCAGGTGGTGCT

GTCCGAGAGGCTGCAGGCCCTGGTGAACAGTCTGTGTGCGGGGCAGTCCCCCTGAGAC

TCGGAGCGGGGCTGACTG

ORF Start: ATG at OItF
26 Stop:
TGA
at 1619 SEQ ID NO: 66 S31 as MW at 56889.8kD

NOVl6a, MAAEQDPEARAGRPLLTDLYQATMALGYWRAGRARDAAEFELFFRRCPFGGAFALVAG

PrOteln Sequence QVSGPLLWQLLETPLLCLVSYASLVATNAARVRLIAGPEKRLLEMGLRRAQGPMGPD

SLHLQLPGGFDSSSNVLAGQLRGVPVAGTLAHSFVTSFSGSEVPPDPMLAPAAGEGPG

VDLAAKAQVWLEQVCAHLGLGVQEPHPGERAAFVAYALAFPRAFQGLLDTYSVWRSGL

PNFLAVALALGELGYRAVGVRLDSGDLLQQAQEIRKVFRAAAAQFQVPWLESVLIWS

NNIDEEALARLAQEGSEVNVIGIGTSWTCPQQPSLGGVYKLVAVGGQPRMKLTEDPE

KQTLPGSKAAFRLLGSDGSPLMDMLQLAEEPVPQAGQELRWPPGAQEPCTVRPAQVE

PLLRLCLQQGQLCEPLPSLAESRALAQLSLSRLSPEHRRLRSPAQYQWLSERLQALV

NSLCAGQSP

SEQ ID NO: 67 1179 by NOVl6b, AGATCTACCAACGCAGCGCGCGTTCGCTTGATCGCAGGGCCAGAGAAGCGGCTGCTAG

DNA

CTACCTGGGCGGCTTCGACAGCAGCAGCAACGTGCTAGCGGGCCAGCTGCGAGGTGTG
SequeriCe CCGGTGGCCGGGACCCTGGCCCACTCCTTCGTCACTTCCTTTTCAGGCAGCGAGGTGC

CCCCTGACCCGATGTTGGCGCCAGCAGCTGGTGAGGGCCCTGGGGTGGACCTGGCGGC

CAAAGCCCAGGTGTGGCTGGAGCAGGTGTGTGCCCACCTGGGGCTGGGGGTGCAGGAG

CCGCATCCAGGCGAGCGGGCAGCCTTTGTGGCCTATGCCTTGGCTTTTCCCCGGGCCT
TCCAGGGCCTCCTGGACACCTACAGCGTGTGGAGGAGTGGTCTCCCCAACTTCCTAGC
GGTGACCTGCTACAGCAGGCTCAGGAGATCCGCAAGGTCTTCCGAGCTGCTGCAGCCC
AGTTCCAGGTGCCCTGGCTGGAGTCAGTCCTCATCGTAGTCAGCAACAACATTGACGA
GGAGGCGCTGGCCCGACTGGCCCAGGAGGGCAGTGAGGTGAATGTCATTGGCATTGGC
ACCAGTGTGGTCACCTGCCCCCAACAGCCTTCCCTGGGTGGCGTCTATAAGCTGGTGG
CCGTGGGGGGCCAGCCACGAATGAAGCTGACCGAGGACCCCGAGAAGCAGACGCTGCC
TGGGAGCAAGGCTGCTTTCCGGCTCCTGGGCTCTGACGGGTCTCCACTCATGGACATG
CTGCAGTTAGCAGAAGAGCCAGTGCCACAGGCTGGGCAGGAGCTGAGGGTGTGGCCTC
CAGGGGCCCAGGAGCCCTGCACCGTGAGGCCAGCCCAGGTGGAGCCACTACTGCGGCT
CTGCCTCCAGCAGGGACAGCTGTGTGAGCCGCTCCCATCCCTGGCAGAGTCTAGAGCC
TTGGCCCAGCTGTCCCTGAGCCGACTCAGCCCTGAGCACAGGCGGCTGCGGAGCCCTG
CACAGTACCAGGTGGTGCTGTCCGAGAGGCTGCAGGCCCTGGTGAACAGTCTGTGTGC
GGGGCAGTCCCCCCTCGAG
ORF Start: AGA at 1 ORF Stop:
~ at 1180 ~~
r~~~~~~~~~~~~~~~~~~

SEQ 393 MW at 41797.4kD
ID NO: 68 aa NOVl6b, RSTNAARVRLIAGPEKRLLEMGLRRAQGPDGGLTASTYSYLGGFDSSSNVLAGQLRGV

174308417 PTOtelri PVAGTLAHSFVTSFSGSEVPPDPMLAPAAGEGPGVDLAAKAQVWLEQVCAHLGLGVQE

SeC]LleriCe PHPGERAAFVAYALAFPRAFQGLLDTYSVWRSGLPNFLAVALALGELGYRAVGVRLDS

GDLLQQAQEIRKVFRAAAAQFQVPWLESVLIWSNNIDEEALARLAQEGSEVNVIGIG

TSWTCPQQPSLGGVYKLVAVGGQPRMKLTEDPEKQTLPGSKAAFRLLGSDGSPLMDM

LQLAEEPVPQAGQELRVWPPGAQEPCTVRPAQVEPLLRLCLQQGQLCEPLPSLAESRA

LAQLSLSRLSPEHRRLRSPAQYQWLSERLQALVNSLCAGQSPLE

SEQ ID NO: 69 1179 by NOV16C, AGATCTACCAACGCAGCGCGCGTTCGCTTGATCGCAGGGCCAGAGAAGCGGCTGCTAG

CTACCTGGGCGGCTTCGACAGCAGCAGCAACGTGCTAGCGGGCCAGCTGCGAGGTGTG
SeCllleriCe CCGGTGGCCGGGACCCTGGCCCACTCCTTCGTCACTTCCTTTTCAGGCAGCGAGGTGC

CCCCTGACCCGATGTTGGCGCCAGCAGCTGGTGAGGGCCCTGGGGTGGACCTGGCGGC

CAAAGCCCAGGTGTGGCTGGAGCAGGTGTGTGCCCACCTGGGGCTGGGGGTGCAGGAG

CCGCATCCAGGCGAGCGGGCAGCCTTTGTGGCCTATGCCTTGGCTTTTCCCCGGGCCT

TCCAGGGCCTCCTGGACACCTACAGCGTGTGGAGGAGTGGTCTCCCCAACTTCCTAGC

AGTCGCCTTGGCCCTGGGAGAGCTGGGCTACCGGGCAGTGGGCGTGAGGCTGGACAGT

GGTGACCTGCTACAGCAGGCTCAGGAGATCCGCAAGGTCTTCCGAGCTGCTGCAGCCC

AGTTCCAGGTGCCCTGGCTGGAGTCAGTCCTCATCGTAGTCAGCAACAACATTGACGA

GGAGGCGCTGGCCCGACTGGCCCAGGAGGGCAGTGAGGTGAATGTCATTGGCATTGGC

ACCAGTGTGGTCACCTGCCCCCAACAGCCTTCCCTGGGTGGCGTCTATAAGCTGGTGG

CCGTGGGGGGCCAGCCACGAATGAAGCTGACCGAGGACCCCGAGAAGCAGACGTTGCC

TGGGAGCAAGGCTGCTTTCCGGCTCCTGGGCTCTGACGGGTCTCCACTCATGGACATG

CTGCAGTTAGCAGAAGAGCCAGTGCCACAGGTTGGGCAGGAGCTGAGGGTGTGGCCTC

CAGGGGCCCAGGAGCCCTGCACCGTGAGGCCAGCCCAGGTGGAGCCACTACTGCGGCT

CTGCCTCCAGCAGGGACAGCTGTGTGAGCCGCTCCCATCCCTGGCAGAGTCTAGAGCC

TTGGCCCAGCTGTCCCTGAGCCGACTCAGCCCTGAGCACAGGCGGCTGCGGAGCCCTG

CACAGTACCAGGTGGTGCTGTCCGAGAGGCTGCAGGCCCTGGTGAACAGTCTGTGTGC

GGGGCAGTCCCCCCTCGAG

ORF Start: AGA at 1 ORF Stop:
at 1180 SEQ ID NO: 70 393 as MW at 41825.4kD

NOV16C, RSTNAARVRLIAGPEKRLLEMGLRRAQGPDGGLTASTYSYLGGFDSSSNVLAGQLRGV

PrOt2lri SeC1L18riCe PHPGERAAFVAYALAFPRAFQGLLDTYSVWRSGLPNFLAVALALGELGYRAVGVRLDS

GDLLQQAQEIRKVFRAAAAQFQVPWLESVLIWSNNIDEEALARLAQEGSEVNVIGIG

TSWTCPQQPSLGGVYKLVAVGGQPRMKLTEDPEKQTLPGSKAAFRLLGSDGSPLMDM

LQLAEEPVPQVGQELRVWPPGAQEPCTVRPAQVEPLLRLCLQQGQLCEPLPSLAESRA

LAQLSLSRLSPEHRRLRSPAQYQVVLSERLQALVNSLCAGQSPLE

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 16B.
Table 16B. Comparison of NOVl6a against NOVl6b through NOVl6c.
Protein Sequence NOVl6a Residues/ Identities/
Match Residues Similarities for the Matched Region NOVl6b 143..531 351/391 (89%) 2..391 353/391 (89%) NOVl6c 143..531 350/391 (89%) 2..391 352/391 (89%) Further analysis of the NOV 16a protein yielded the following properties shown in Table 16C.
Table 16C.
Protein Sequence Properties NOVl6a PSort 0.4500 probability located in cytoplasm; 0.3000 probability located in microbody analysis:(peroxisome); 0.2864 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space SignalP No Known Signal Sequence Predicted analysis:

A search of the NOV 16a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 16D.
Table 16D. Geneseq Results for NOVl6a NOVl6a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value ResiduesRegion AAG33687 Arabidopsis thaliana protein14..531 231/547 (42%)e-113 fragment SEQ ID NO: 40861 - Arabidopsis4..548 330/547 (60%) thaliana, 553 aa. [EP1033405-A2, SEP-2000]

AAG33686 Arabidopsis thaliana protein14..531 231/547 (42%)e-113 fragment SEQ ID NO: 40860 - Arabidopsis25..569 330/547 (60%) thaliana, 574 aa. [EP1033405-A2, SEP-2000]

AAG33685 Arabidopsis thaliana protein14..531 231/547 (42%)e-113 fragment SEQ ID NO: 40859 - Arabidopsis42..586 330/547 (60%) thaliana, 591 aa. [EP1033405-A2, SEP-2000]

AAY74114Human prostate tumor EST fragment 197/198 (99%) e-109 334..531 derived protein #301 - Homo Sapiens,198/198 (99%) 26..223 223 aa. [DE 19820190-A 1, 04-NOV-1999]

AAG29216Arabidopsis thaliana protein fragment200/468 (42%) 1e-95 14..474 SEQ ID NO: 34723 - Arabidopsis 278/468 (58%) 4..432 thaliana, 435 aa. [EP1033405-A2, SEP-2000]

In a BLAST
search of public sequence databases, the NOV
16a protein was found to have homology to the proteins shown in the BLASTP data in Table 16E.
Table 16E.
Public BLASTP
Results for NOVl6a Protein NOVl6a Identities/
Accession Protein/Organism/Length Residues/
Similarities for Expect Number Match the Matched Value Residues Portion Q9BRG0 HYPOTHETICAL 58.1 KDA 1..531 514/539 (95%)0.0 PROTEIN - Homo Sapiens 5..542 516/539 (95%) (Human), 542 as (fragment).

Q9VQX4 CG3714 PROTEIN - Drosophila 234/525 (44%)e-120 14..531 melanogaster (Fruit fly), 541 330/525 (62%) aa. 13..536 080459 AT2G23420 PROTEIN - 14..531 231/547 (42%)e-112 Arabidopsis thaliana (Mouse-ear330/547 (60%) 25..569 cress), 574 aa.

AAK68525 HYPOTHETICAL 57.8 KDA 13..445 198/443 (44%)e-101 PROTEIN - Caenorhabditis 9..449290/443 (64%) elegans, 511 aa.

Q95XX1 HYPOTHETICAL 59.9 KDA 13..445 198/443 (44%)e-101 PROTEIN - Caenorhabditis 29..469290/443 (64%) elegans, 531 aa.

PFam analysis predicts that the NOV 16a protein contains the domains shown in the Table 16F.
Table 16F.
Domain Analysis of NOVl6a Identitiesl Pfam DomainNOVl6a Match Similarities Expect Region Value for the Matched Region No Significant Matches Found EXAMPLE 17.
The NOV 17 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 17A.

Table 17A. NOV17 Sequence Analysis SEQ ID NO: 71 572 by NOVl7a, CCGTGGTGCACGCGCTGCCCCGCATCAACCGCATGGTGCTGTGCTACCTCATCCGCTT

CTGGCCATGGTGATGGCGCCCAACTGCTTGCGCTGCCAGTCCGACGACCCGCGCGTCA
SequeriCe TCTTCGAGAACACCCGCAAGGAGATGTCCTTCCTGCGGGTGCTCATCCAGCACCTGGA

CACCAGCTTCATGGAGGGTGTGCTGTAGCGGGGGCGCCCGGGGACAGGAGGGATGTCC

TGCCGCCCCCAGCCAGGCCGAACTCCGCACTCGCTCTCCCGGCAGAGGGGTCAGAATC

GCCCGGCCCAGCCCTGGAGCCCCCTCCACTCCCCCAGGCCCCTGGCCCCGGCGCTCCC

CACGTCTTCTGCCTGGTCTGAGGGTGTAGCCAGGGCACAGCAGCGGCGGGGAGGGCGC

CTCTGGCCCCCCACCTCACGGCCAGTTCCCGCGGGCACCGCCTCGCCCTCCGCTGGCC

GCGGGTCAGCTCCGAGAAAGTGCCTTCTGTAGCTTCATTTTATATTAATT

ORF Start: ATG at 33 ORF
Stop:
TAG
at SEQ ID NO: 72 75 MW at 8638.2kD
as NOVl7a, MVLCYLIRFLQVFVQPANVAVTKMDVSNLAMVMAPNCLRCQSDDPRVIFENTRKEMSF

CG59368-01 PrOteln LRVLIQHLDTSFMEGVL

Sequence Further analysis of the NOV 17a protein yielded the following properties shown in Table 17B.
Table 17B. Protein Sequence Properties NOVl7a PSort 0.8134 probability located in mitochondrial intermembrane space; 0.5255 analysis: probability located in mitochondrial matrix space; 0.2672 probability located in lysosome (lumen); 0.2537 probability located in mitochondrial inner membrane SignalP ~ Likely cleavage site between residues 20 and 21 analysis:
A search of the NOV 17a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 17C.
Table 17C.
Geneseq Results for NOVl7a NOVl7a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value ResiduesRegion AAE03048Human preoptic regulatory 1..75 75/75 (100%)1e-37 factor-2 (hPORF-2) protein #1 - 1..75 75/75 (100%) Homo Sapiens, 75 aa. [W0200142464-A2, 2001 ]

In a BLAST search of public sequence databases, the NOV 17a protein was found to have homology to the proteins shown in the BLASTP data in Table 17D.
Table 17D. Public BLASTP Results for NOVl7a Protein NOVl7a Identities/

AccessionProtein/Organism/Length Residues/SimilaritiesExpect for Match the Matched Value Number Residues Portion Q9COH5 KIAA1688 PROTEIN - Homo 1..75 75/75 (100%)4e-37 Sapiens (Human), 1094 1020..109475/75 (100%) as (fragment).

P18890 Putative preoptic regulatory1..75 74/75 (98%) Se-37 factor-2 precursor (PORF-2) - Rattus1..75 75/75 (99%) norvegicus (Rat), 75 aa.

Q9VDE9 CG3421 PROTEIN - Drosophila1..75 48/75 (64%) 2e-21 melanogaster (Fruit fly),1235..130958/75 (77%) 1309 aa.

PFam analysis predicts that the NOV 17a protein contains the domains shown in the Table 17E.
Table 17E. Domain Analysis of NOVl7a Identities/
Pfam Domain NOVl7a Match Region Similarities Expect Value for the Matched Region No Significant Matches Found EXAMPLE 18.
The NOV 18 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 18A.
Table 18A. NOV18 0 ~ SEQ ID NO: 73 ~ 1452 by NOVlBa, ATCCTGCCCCGCAGGGTGACCCTGTTTGCAGCACGATGTCTGAAGAAGAGGCGGCTCA

DNA

GCTCTGCCCCTGGTCAGGGCCACGTGCACCGCGGTCTGCGATGTTTACAGTGCAGCCA
SequeriCe AGGACAGGCACCCGCTGCTGGGCTCCGCCTGCCGCCTGGCTGAGAACTGCGTGTGCGG

CCTGACCACCCGTGCCCTGGACCACGCCCAGCCGCTGCTCGAGCACCTGCAGCCCCAG

GTGGCCACTATGAACAGCCTCGCCTGCAGGGGCCTGGACAAGCTGGAAGAGAAGCTTC

CCTTTCTCCAGCAACCTTCGGAGACGGTAGTGACCTCAGCCAAGGACGTGGTGGCCAG

CAGTGTCACGGGTGTGGTGGACCTGGCCCGGAGGGGCCGGCGCTGGAGCGTGGAGCTG

AAGCGCTCCGTGAGCCATGCTGTGGATGTTGTACTGGAAAAATCAGAGGAGCTGGTGG

ATCACTTCCTGCCCATGACGGAGGAAGAGCTCGCGGCACTGGCGGCTGAGGCTGAAGG

CCCTGAAGTGGGTTCGGTGGAGGATCAGAGGAGACAGCAGGGCTACTTTGTGCGCCTC

GGCTCCCTGTCAGCACGGATCCGCCACCTGGCCTACGAGCACTCTGTGGGGAAACTGA

GGCAGAGCAAACACCGTGCCCAGGACACCCTGGCCCAGCTGCAGGAGACGCTGGAGCT

GATAGACCACATGCAGTGTGGGGTGACCCCCACCGCCCCGGCCTGCCCTGGGAAGGTG

CACGAGCTGTGGGGGGAATGGGGCCAGCGCCCTCCGGAGAGCCGCCGCCGGAGCCAGG

TGGAGCTGGAGACGCTGGTGCTGTCCCGCAGCCTGACCCAGGAGCTGCAGGGCACGGT

AGAGGCTCTGGAGTCCAGCGTGCGGGGCCTGCCCGCCGGCGCCCAGGAGAAGGTGGCT

GAGGTGCGGCGCAGTGTGGATGCCCTGCAGACCGCCTTCGCTGATGCCCGCTGCTTCA

GGGACGTGCCAGCGGCCGCGCTGGCCGAGGGCCGGGGTCGCGTGGCCCACGCGCACGC

CTGCGTGGACGAGCTGCTGGAGCTGGTGGTGCAGGCCGTGCCGCTGCCCTGGCTGGTG

GGACCCTTCGCGCCCATCCTTGTGGAGCGACCCGAGCCCCTGCCCGACCTGGCGGACC

TGGTGGACGAGGTCATCGGGGGCCCTGACCCCCGCTGGGCGCACCTGGACTGGCCGGC
CCAGCAGAGAGCCTGGGAGGCAGAGCACAGGGACGGGAGTGGGAATGGGGATGGGGAC
AGGATGGGTGTTGCCGGGGACATCTGCGAGCAGGAACCCGAGACCCCCAGCTGCCCGG
TCAAGCACACCCTGATGCCCGAGCTGGACTTCTGACCCATGGGCCAGTGGAGGCGGGG
AG
~ORF~Start: ~ATG at 36 ORF Stop:
TGA
at 1425 SEQ ID NO: 74 ~ 463 as MW at 50804.9kD

NOV 18a, MSEEEAAQI PRSSVWEQDQQNWQRWALPLVRATCTAVCDWSAAKDRHPLLGSACR

CGS8628-O1 PrOtelri L~NCVCGLTTRALDHAQPLLEHLQPQVATMNSLACRGLDKLEEKLPFLQQPSETVVT

Se LleriCe SAKDWASSVTGVVDLARRGRRWSVELKRSVSHAVDWLEKSEELVDHFLPMTEEELA

ALAAEAEGPEVGSVEDQRRQQGYFVRLGSLSARIRHLAYEHSVGKLRQSKHRAQDTLA

QLQETLELIDHMQCGVTPTAPACPGKVHELWGEWGQRPPESRRRSQVELETLVLSRSL

TQELQGTVEALESSVRGLPAGAQEKVAEVRRSVDALQTAFADARCFRDVPAAALAEGR

GRVAHAHACVDELLELWQAVPLPWLVGPFAPILVERPEPLPDLADLVDEVIGGPDPR

WAHLDWPAQQRAWEAEHRDGSGNGDGDRMGVAGDICEQEPETPSCPVKHTLMPELDF

SEQ ID NO: 7S 978 by NOVlBb, AGATCTGACCAGCAGAACGTGGTGCAGCGTGTGGTGGCTCTGCCCCTGGTCAGGGCCA

CTCCGCCTGCCGCCTGGCTGAGAACTGCGTGTGCGGCCTGACCACCCGTGCCCTGGAC
S8C1L1eriCe CACGCCCAGCCGCTGCTCGAGCACCTGCAGCCCCAGCTGGCCACTATGAACAGCCTCG

CCTGCAGGGGCCTGGACAAGCTGGAAGAGAAGCTTCCCTTTCTCCAGCAACCTTCGGA

GACGGTGGTGACCTCAGCCAAGGACGTGGTGGCCAGCAGTGTCACGGGTGTGGTGGAC

CTGGCCCGGAGGGGCCGGCGCTGGAGCGTGGAGCTGAAGCGCTCCGTGAGCCATGCTG

TGGATGTTGTACTGGAAAAATCAGAGGAGCTGGTGGATCACTTCCTGCCCATGACGGA

GGAAGAGCTCGCGGCACTGGCGGCTGAGGCTGAAGGCCCTGAAGTGGGTTCGGTGGAG

GATCAGAGGAGACAGCAGGGCTACTTTGTGCGCCTCGGCTCCCTGTCAGCACGGATCC

GCCACCTGGCCTACGAGCACTCTGTGGGGAAACTGAGGCAGAGCAAACACCGTGCCCA

GGACACCCTGGCCCAGCTGCAGGAGACGCTGGAGCTGATAGACCACATGCAGTGTGGG

GTGACCCCCACCGCCCCGGCCCGCCCTGGGAAGGTGCACGAGCTGTGGGGGGAATGGG

GCCAGCGCCCTCCGGAGAGCCGCCGCCGGAGCCAGGCAGAGCTGGAGACGCTGGTGCT

GTCCCGCAGCCTGACCCAGGAGCTGCAGGGCACGGTAGAGGCTCTGGAGTCCAGCGTG

CGGGGCCTGCCCGCCGGCGCCCAGGAGAAGGTGGCTGAGGTGCGGCGCAGTGTGGATG

CCCTGCAGACCGCCTTCGCTGATGCCCGCTGCTTCAGGGACGTGGTCGAC

ORF Start: AGA at 1 ORF Stop:

SEQ ID NO: 76 326 as MW at 3S9S4.4kD

NOV 18b, RSDQQNWQRWALPLVRATCTAVCDWSAAKDRHPLLGSACRLAENCVCGLTTRALD

1742283SO Pl'Otelri HAQPLLEHLQPQLATMNSLACRGLDKLEEKLPFLQQPSETVVTSAKDWASSVTGVVD

S8 lleriCe L~RGRRWSVELKRSVSHAVDVVLEKSEELVDHFLPMTEEELAALAAEAEGPEVGSVE

DQRRQQGYFVRLGSLSARIRHLAYEHSVGKLRQSKHRAQDTLAQLQETLELIDHMQCG

VTPTAPARPGKVHELWGEWGQRPPESRRRSQAELETLVLSRSLTQELQGTVEALESSV

RGLPAGAQEKVAEVRRSVDALQTAFADARCFRDVVD

SEQ ID NO: 77 978 by NOV18C, ~AGATCTGACCAGCAGAACGTGGTGCAGCGTGTGGTGGCTCTGCCCCTGGTCAGGGCCA

CTCCGCCTGCCGCCTGGCTGAGAACTGCGTGTGCGGCCTGACCACCCGTGCCCTGGAC
SeClLleriCe CACGCCCAGCCGCTGCTCGAGCACCTGCAGCCCCAGCTGGCCACTATGAACAGCCTCG
CCTGCAGGGGCCTGGACAAGCTGGAAGAGAAGCTTCCCTTTCTCCAGCAACCTTCGGA
GACGGTGGTGACCTCAGCCAAGGACGTGGTGGCCAGCAGTGTCACGGGTGTGGTGGAC
CTGGCCCGGAGGGGCCGGCGCTGGAGCGTGGAGCTGAAGCGCTCCGTGAGCCATGCTG
TGGATGTTGTACTGGAAAAATCAGAGGAGCTGGTGGATCACTTCCTGCCCATGACGGA
GGAAGAGCTCGCGGCACTGGCGGCTGAGGCTGAAGGCCCTGAAGTGGGTTCGGTGGAG
GATCAGAGGAGACAGCAGGGCTACTTTGTGCGCCTCGGCTCCCTGTCAGCACGGATCC
GCCACCTGGCCTACGAGCACTCTGTGGGGAAACTGAGGCAGAGCAAACACCGTGCCCA
GGACACCCTGGCCCAGCTGCAGGAGACGCTGGAGCTGATAGACCACATGCAGTGTGGG
GTGACCCCCACCGCCCCGGCCCGCCCTGGGAAGGTGCACGAGCTGTGGGGGGAATGGG

GCCAGCGCCCTCCGGAGAGCCGCCGCCGGAGCCAGGCAGAGCTGGAGACGCTGGTGCT

GTCCCGCAGCCTGACCCAGGAGCTGCAGGGCACGGTAGAGGCTCTGGAGTCCAGCGTG

TGGGGCCTGCCCGCCGGCGCCCAGGAGAAGGTGGCTGAGGTGCGGCGCAGTGTGGATG

CCCTGCAGACCGCCTTCGCTGATGCCCGCTGCTTCAGGGACGTGGTCGAC

ORF Start: AGA at OItF
1 Stop:

SEQ ID NO: 78 326 as MW at 35984.41cD

NOV 18C, RSDQQNWQRWALPLVRATCTAVCDW
SAAKDRH PLLGSACRLAENCVCGLTTRALD

PIOtelri Se uenCe L~RGRRWSVELKRSVSHAVDWLEKSEELVDHFLPMTEEELAALAAEAEGPEVGSVE
q DQRRQQGYFVRLGSLSARIRHLAYEHSVGKLRQSKHRAQDTLAQLQETLELIDHMQCG

VTPTAPARPGKVHELWGEWGQRPPESRRRSQAELETLVLSRSLTQELQGTVEALESSV

WGLPAGAQEKVAEVRRSVDALQTAFADARCFRDVVD

SEQ ID NO: 79 1401 by NOVlBd, AGATCTATGTCTGAAGAAGAGGCGGCTCAGATCCCCAGATCCAGTGTGTGGGAGCAGG

DNA

CGCGGTCTGCGATGTTTACAGTGCAGCCAAGGACAGGCACCCGCTGCTGGGCTCCGCC
SequeriCe TGCCGCCTGGCTGAGAACTGCGTGTGCGGCCTGACCACCCGTGCCCTGGACCACGCCC

AGCCGCTGCTCGAGCACCTGCAGCCCCAGCTGGCCACTATGAACAGCCTCGCCTGCAG

GGGCCTGGACAAGCTGGAAGAGAAGCTTCCCTTTCTCCAGCAACCTTCGGAGACGGTG

GTGACCTCAGCCAAGGACGTGGTGGCCAGCAGTGTCACGGGTGTGGTGGACCTGGCCC

GGAGGGGCCGGCGCTGGAGCGTGGAGCTGAAGCGCTCCGTGAGCCATGCTGTGGATGT

TGTACTGGAAAAATCAGAGGAGCTGGTGGATCACTTCCTGCCCATGACGGAGGAAGAG

CTCGCGGCACTGGCGGCTGAGGCTGAAGGCCCTGAAGTGGGTTCGGTGGAGGATCAGA

GGAGACAGCAGGGCTACTTTGTGCGCCTCGGCTCCCTGTCAGCACGGATCCGCCACCT

GGCCTACGAGCACTCTGTGGGGAAACTGAGGCAGAGCAAACACCGTGCCCAGGACACC

CTGGCCCAGCTGCAGGAGACGCTGGAGCTGATAGACCACATGCAGTGTGGGGTGACCC

CCACCGCCCCGGCCCGCCCTGGGAAGGTGCACGAGCTGTGGGGGGAATGGGGCCAGCG

CCCTCCGGAGAGCCGCCGCCGGAGCCAGGCAGAGCTGGAGACGCTGGTGCTGTCCCGC

AGCCTGACCCAGGAGCTGCAGGGCACGGTAGAGGCTCTGGAGTCCAGCGTGTGGGGCC

TGCCCGCCGGCGCCCAGGAGAAGGTGGCTGAGGTGCGGCGCAGTGTGGATGCCCTGCA

GACCGCCTTCGCTGATGCCCGCTGCTTCAGGGACGTGCCAGCGGCCGCGCTGGCCGAG

GGCCGGGGTCGCGTGGCCCACGCGCACGCCTGCGTGGACGAGCTGCTGGAGCTGGTGG

TGCAGGCCGTGCCGCTGCCCTGGCTGGTGGGACCCTTCGCGCCCATCCTTGTGGAGCG

ACCCGAGCCCCTGCCCGACCTGGCGGACCTGGTGGACGAGGTCATCGGGGGCCCTGAC

CCCCGCTGGGCGCACCTGGACTGGCCGGCCCAGCAGAGAGCCTGGGAGGCAGAGCACA

GGGACGGGAGTGGGAATGGGGATGGGGACAGGATGGGTGTTGCCGGGGACATCTGCGA

GCAGGAACCCGAGACCCCCAGCTGCCCGGTCAAGCACACCCTGATGCCCGAGCTGGAC

TTCGTCGAC

OItF Start: AGA ORF Stop:
at 1 SEQ ID NO: 80 467 as MW at S 1331.41cD

NOVlBd, RSMSEEEAAQIPRSSVWEQDQQNWQRWALPLVRATCTAVCDVYSAAKDRHPLLGSA

PrOtelri SequeriCe VTSAKDWASSVTGWDLARRGRRWSVELKRSVSHAVDWLEKSEELVDHFLPMTEEE

LAALAAEAEGPEVGSVEDQRRQQGYFVRLGSLSARIRHLAYEHSVGKLRQSKHRAQDT

LAQLQETLELIDHMQCGVTPTAPARPGKVHELWGEWGQRPPESRRRSQAELETLVLSR

SLTQELQGTVEALESSVWGLPAGAQEKVAEVRRSVDALQTAFADARCFRDVPAAALAE

GRGRVAHAHACVDELLELWQAVPLPWLVGPFAPILVERPEPLPDLADLVDEVIGGPD

PRWAHLDWPAQQRAWEAEHRDGSGNGDGDRMGVAGDICEQEPETPSCPVKHTLMPELD

FVD

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 18B.
Table 18B. Comparison of NOVlBa against NOVl8b through NOVl8d.

NOVlBa Residues/Identities/

Protein SequenceMatch ResiduesSimilarities for the Matched Region NOVl8b 18..339 ~ 307/322 (95%) 3..324 308/322 (95%) NOVl8c 18..339 306/322 (95%) 3..324 307/322 (95%) NOVl8d 1..463 447/463 (96%) 3..465 448/463 (96%) Further analysis of the NOV 18a protein yielded the following properties shown in Table 18C.
Table 18C. Protein Sequence Properties NOVlBa PSort 0.3000 probability located in microbody (peroxisome); 0.3000 probability analysis: located in nucleus; 0.1000 probability located in mitochondrial matrix space;
0.1000 probability located in lysosome (lumen) SignalP No Known Signal Sequence Predicted analysis:
A search of the NOVl8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 18D.
Table 18D.
Geneseq Results for NOVl8a NOVl8a Identities/

Geneseq Protein/Organism/Length [Patent SimilaritiesExpect #, Residues/ for IdentifierDate] Match the Matched Value Residues Region AAY67240 Human adipophilin-like protein 163/407 (40%)1e-77 19..385 (HALP) amino acid sequence - Homo234/407 (57%) 22..428 Sapiens, 434 aa. [US5989820-A, NOV-1999]

AAW59883 Amino acid sequence of the cDNA 149/411 (36%)4e-64 19..388 clone ADF (HFKFY79) - Homo 22..431223/411 (54%) sapiens, 452 aa. [W09831800-A2, 23-JL1L-1998]

AAM25962 Human protein sequence SEQ ID 116/117 (99%)4e-62 ' 1..117 N0:1477 - Homo Sapiens, 139 aa. 117/117 (99%) 23..139 [W0200153455-A2, 26-JCTL-2001]

AAY99534 Human adipocyte-specific 12..384 140/416 (33%)1e-59 differentiation-related protein 222/416 (52%) ADRP - 2..411 Homo Sapiens, 437 aa.

[W0200031532-A1, 02-JCTN-2000]

AAW53264 Human adipocyte-specific 12..384 140/416 (33%)1e-59 differentiation-related 2..411 222/416 (52%) protein - Homo sapiens, 437 aa. [US5739009-A, APR-1998]

In a BLAST search of public sequence databases, the NOV 18a protein was found to have homology to the proteins shown in the BLASTP data in Table 18E.
Table 18E. Public BLASTP
Results for NOVl8a Protein NOVl8a Identities/

AccessionProtein/Organism/Length Residues/SimilaritiesExpect for Match the MatchedValue Number Residues Portion Q9D6M0 2310076L09RIK PROTEIN - 1..463 329/463 0.0 Mus (71 %) musculus (Mouse), 448 aa. 1..448 368/463 (79%) Q9BS03 CARGO SELECTION PROTEIN 19..385 163/407 4e-77 (40%) (MANNOSE 6 PHOSPHATE 22..428 234/407 (57%) RECEPTOR BINDING PROTEIN) -Homo sapiens (Human), 434 aa.

060664 Cargo selection protein 19..385 163/407 6e-77 TIP47 (47 lcDa (40%) mannose 6-phosphate receptor-22..428 234/407 binding (57%) protein) (47 lcDa MPR-binding protein) (Placental protein 17) - Homo sapiens (Human), 434 aa.

Q9DBG5 1300012C15RIK PROTEIN (RIKEN19..385 160/411 4e-73 (38%) CDNA 1300012015 GENE) - 22..432 232/411 Mus (SS%) musculus (Mouse), 437 aa.

Q9CZK1 1300012C15RIK PROTEIN - 19..385 160/411 6e-73 Mus (38%) musculus (Mouse), 437 aa. 22..432 232/411 (55%) PFam analysis predicts that the NOV 18a protein contains the domains shown in the Table 18F.
Table 18F. Domain Analysis of NOVlBa Identities/
Pfam Domain NOVl8a Match Similarities Expect Region for the Matched Value Region Man-6-P_rece : domain 1 156..168 9/13 69% 0.7 of 1 p I 9/13 (69°/) perilipin: domain 1 of 1 10..369 139/411 (34%) 1.4e-76 240/411 (58%) EXAMPLE 19.
The NOV 19 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 19A.
Table 19A. NOV19 Sequence Analysis SEQ ID NO: 81 ~ 774 by NOVl9a, ~GTAGAGTTTTTCAGGTTGCTCCTGGAAACCATGCCGAAAGTAGTGTCTCGGTCAGTAG
'CGS9342-O1 DNA TCTGCTCTGACACTCGGGACCGGGAGGAATATGACGACGGCGAGAAGCCCCTCCATGT
GTACTACTGTTTGTGCGGCCAGGTGGTCCTAGTGCTGGACTGTCAGTTAGAGAAATTG
SeqlleriCe CCCATGAGGCCCCGGGACCGGTCCCGTGTGATTGATGCTGCCAAACATGCCCATAAGT
TTTGTAACACAGAAGACGAAGAGACTATGTATCTGCGGAGACCTGAAGGCATTGAACT
ACAGTACAGAAAGAAATGTGCAAAGTGTGGACTGCTGCTCTTCTACCAATCCCAGCCG
AAGAATGCTCCCGTTACCTTCATTGTGGATGGAGCAGTCGTCAAGTTTGGCCAGGGCT
TTGGGAAAACGAACATATATACTCAGAAACAAGAGCCTCCTAAGAAGGTGATGATGAC
CAAACGGACCAAAGACATGGGCAAGTTCAGTTCTGTCACTGTGTCTACCATTGATGAA
GAGGAAGAGGAGATTGAGGCTAGGGAAGTTGCTGACTCGTATGCACAGAATGCCAAAG
TGATTGAAAAACAGCTGGAGCGCAAAGGCATGAGCAAGAGGCCACTGCAAGAGCTGGC
TGAATGGGAACCCCAGGAAAAGAGGACATATGACACAGGTTCTCCCTCTGCAAAAAAG
TGGCAGATGCGTGGCTCAGGGGCCTTCCACTGTCCAGGTCCTCCTCAGATGGCCCTGG
GAATGAGCGGCCACCATTAA
ORF Start: ATG at 31 O1ZF Stop: TAA at 772 SEQ ID NO: 82 247 as MW at 28211.11cD
NOV 19a, MPKWSRSWCSDTRDREEYDDGEKPLHWYCLCGQVVLVLDCQLEKLPMRPRDRSRV

PrOteln Sequence GAWKFGQGFGKTNIYTQKQEPPKKVMMTKRTKDMGKFSSVTVSTIDEEEEEIEAREV

ADSYAQNAKVIEKQLERKGMSKRPLQELAEWEPQEKRTYDTGSPSAKKWQMRGSGAFH

CPGPPQMALGMSGHH

Further analysis of the NOV 19a protein yielded the following properties shown in Table 19B.
Table 19B. Protein Sequence Properties NOVl9a PSort 0.4500 probability located in cytoplasm; 0.3600 probability located in analysis: mitochondrial matrix space; 0.1000 probability located in lysosome (lumen);
0.0000 probability located in endoplasmic reticulum (membrane) SignalP ~ No Known Signal Sequence Predicted analysis:
A search of the NOV 19a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 19C.
Table 19C.
Geneseq Results for NOVl9a NOVl9a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect (Patent #, for IdentifierDate) Match the Matched Value ResiduesRegion AAG01784 Human secreted protein, 1..86 85/86 (98%)3e-46 SEQ ID NO:

5865 - Homo sapiens, 87 1..86 86/86 (99%) aa.

[EP1033401-A2, 06-SEP-2000]

AAM41425 Human polypeptide SEQ ID 139..21565/77 (84%)4e-28 - Homo Sapiens, 92 aa. 9..85 69/77 (89%) [W0200153312-A1, 26-JUL-2001]

AAM39639 Human polypeptide SEQ ID 143..21563/73 (86%)6e-27 - Homo Sapiens, 80 aa. 1..73 66/73 (90%) [W0200153312-A1, 26-JUL-2001]

AAG60283 Arabidopsis thaliana protein1..119 44/127 (34%)2e-09 fragment SEQ ID NO: 78065 - Arabidopsis1..122 64/127 (49%) thaliana, 236 aa. [EP1033405-A2, SEP-2000]

AAG59843 Arabidopsis thaliana protein1..119 42/123 (34%)8e-09 fragment SEQ ID NO: 77448 - Arabidopsis1..116 63/123 (51%) thaliana, 230 aa. [EP1033405-A2, SEP-2000]

In a BLAST search of public sequence databases, the NOV 19a protein was found to have homology to the proteins shown in the BLASTP data in Table 19D.
Table 19D. Public BLASTP Results for NOVl9a Protein NOVl9a Identities/

AccessionProtein/OrganismlLength Residues/Similarities Expect for Number Match the Matched Value ResiduesPortion Q9H5V9 CDNA: FLJ22965 FIS, CLONE1..215 202/215 (93%)e-114 KAT10418 - Homo Sapiens 1..215 206/215 (94%) (Human), 222 aa.

AAH21479 HYPOTHETICAL 25.6 KDA 1..215 201/215 (93%)e-113 PROTEIN - Mus musculus 1..215 205/215 (94%) (Mouse), 222 aa.

Q9CWC1 C330007P06RIK PROTEIN 1..202 197/202 (97%)e-111 - Mus musculus (Mouse), 250 1..202 198/202 (97%) aa.

Q9V412 BG:DS00941.3 PROTEIN 1..193 106/220 (48%)2e-50 -Drosophila melanogaster 1..218 145/220 (65%) (Fruit fly), 247 aa.

Q95Q06 Y66D12A.8 PROTEIN - 13..194 79/187 (42%) 1e-30 Caenorhabditis elegans, 29..207 114/187 (60%) 244 aa.

PFam analysis predicts that the NOVl9a protein contains the domains shown in the Table 19E.

Table 19E.
Domain Analysis of NOVl9a Identities/

Pfam DomainNOVl9a Match Similarities Expect Region Value for the Matched Region No Significant Matches Found ExAII~PLE 20.
The NOV20 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 20A.
Table 20A. NOV20 Sequence Analysis SEQ ID NO: 83 324 by NOV2Oa, ATTTTTTTGTTGTTATTGTTGTAGATATGTGGTTTCCCCATGTTGCCAGCTGGCCTCG

CG59486-O1 DNA ~CTCCTGGCCTCAAGATCCACCCGCCTCGACCTCCCAAAGGCCCAGCCCCTCTCTTT

CCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTGTTTTT
Sequence AAAGGCCAGGCGCAGTGGCTCATGTCTGTAATCCCAGCACTCTGGGAGGCCAAGGCAG

GCAGATCACAAGGTCAGGAGATCAAGACCATCCTGGCTAACACAGTGAAACCCCATCT

CTACTAAAAAATACAAAAAAAAATTAGCCAGGCG

ORF Start: ATG at 40 ORF
Stop:
TAA
at SEQ ID NO: 84 85 MW at 9476.2kD
as NOV2Oa, MLPAGLELLASRSTRLDLPKAQPLSFLPSFLPSFLPSFLVFKKKKKGQAQWLMSVIPA

CGS9486-O1 PrOteln LWEAKAGRSQGQEIKTILANTVKPHLY

Sequence Further analysis of the NOV20a protein yielded the following properties shown in Table 20B.
Table 20B.
Protein Sequence Properties NOV20a PSort 0.6238 probability located in microbody (peroxisome);
0.6000 probability analysis:located in nucleus; 0.3600 probability located in mitochondria) matrix space;

0.1830 probability located in lysosome (lumen) SignalP No Known Signal Sequence Predicted analysis:

A search of the NOV20a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 20C.
Table 20C. Geneseq Results for NOV20a NOV20a Identities) Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities Expect Identifier Date] Match for the Value Residues Matched Region AAB95050 Human protein sequence 35..85 38/51 (74%)4e-15 SEQ ID

N0:16847 - Homo Sapiens, 62..112 42/51 (81 112 aa. %) [EP 1074617-A2, 07-FEB-2001 ]

ABB11422 Human Zn finger protein 47..85 32/39 (82%)1e-12 homologue, SEQ ID N0:1792 - Homo Sapiens,632..67035/39 (89%) aa. [W0200157188-A2, 09-AUG-2001 ]

AAM85296 Human immune/haematopoietic37..84 35/49 (71%)1e-12 antigen SEQ ID N0:12889 - Homo 19..67 41/49 (83%) Sapiens, 81 aa. [W0200157182-A2, 09-AUG-2001 ]

AAM94124 Human reproductive system 41..85 33/45 (73%)3e-12 related antigen SEQ ID NO: 2782 63..107 38/45 (84%) - Homo Sapiens, 107 aa. [W0200155320-A2, 02-AUG-2001 ]

AAM91494 Human immune/haematopoietic49..85 32/37 (86%)3e-12 antigen SEQ ID N0:19087 - Homo 22..58 34/37 (91%) sapiens, 58 aa. [W0200157182-A2, 09-AUG-2001 ]

In a BLAST search of public sequence databases, the NOV20a protein was found to have homology to the proteins shown in the BLASTP data in Table 20D.
Table 20D. Public BLASTP Results for NOV20a Protein NOV20a Identities/

AccessionProtein/Organism/Length Residues/SimilaritiesExpect for Number Match the Matched Value ResiduesPortion Q9UI59 PR00478 - Homo Sapiens 8..85 50/82 (60%) 4e-18 (Human), 87 aa. 7..87 59/82 (70%) P39189 Alu subfamily SB sequence47..85 30/39 (76%) 1e-10 contamination warning 1..39 35/39 (88%) entry - Homo sapiens (Human), 587 aa.

P39192 Alu subfamily SC sequence47..85 29/39 (74%) Se-10 contamination warning 1..39 34/39 (86%) entry - Homo Sapiens (Human), 585 aa.

P39191 Alu subfamily SB2 sequence47..85 29/39 (74%) 9e-10 contamination warning 1..39 33/39 (84%) entry - Homo Sapiens (Human), 603 aa.

P39190 Alu subfamily SB1 sequence47..85 28/39 (71%) 3e-09 contamination warning 1..39 33/39 (83%) entry - Homo Sapiens (Human), 587 aa.

PFam analysis predicts that the NOV20a protein contains the domains shown in the Table 20E.
Table 20E.
Domain Analysis of NOV20a Identities/

Pfam DomainNOV20a Match RegionSimilarities Expect Value for the Matched Region No Significant Matches Found EXAMPLE 21.
The NOV21 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 21A.
.r Table 21A. NOV21 Sequence Analysis SEQ ID NO: 85 1572 by NOV2la, GGTGTGCAGGATATAAGGTTGGACTTCCAGACCCACTGCCCGGGAGAGGAGAGGAGCG

DNA

TGGGAAGATGGCCGGCCCGTGGACCTTCACCCTTCTCTGTGGTTTGCTGGCAGCCACC
Sequence TTGATCCAAGCCACCCTCAGTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCA

AAGAAAAGCTGACACAGGAGCTGAAGGACCACAACGCCACCAGCATCCTGCAGCAGCT

GCCGCTGCTCAGTGCCATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGC

CTGGTGAACACCGTCCTGAAGCACATCATCTGGCTGAAGGTCATCACAGCTAACATCC

TCCAGCTGCAGGTGAAGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCT

GGACATGGTGGCTGGATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATG

ACGACTGAGGCCCAAGCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCC

TGGTCCTCAGTGACTGTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAA

GCTCTCCTTCCTGGTGAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCC

CTGCCCAATCTAGTGAAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCA

TGTATGCAGACCTCCTGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCT

GGAGTTTGACCTTCTGTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGG

GCCAAGTTGTTGGACTCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTT

CCCTGACAATGCCCACCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCACCCGTT

CAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGTGGCTGCTGTGCTCTCTCCA

GAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAGAGTGCCCATCGGCTGAAGT

CAAGCATCGGGCTGATCAATGAAAAGGAAGCCAGCTCGGAAGCTCAGTTTTACACCAA

AGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCTGATG

AACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAGATCA

TCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAGTGTC

ATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGCCCTT

GTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGTGAAGACTTG

GATGGCAGCCATCAGGGAAGGCTGGGTCCCAGTTGGGAGTATGGGTGTGAGCTCTATA

GACCATCCCTCTCTGCAATCAATAAACACTTGCCTGTGAAAAAi~AAAAAAAAATAAAA
AAAAAA

OItF Start: ATG at 124 OItF Stop: TGA
at 1441 SEQ ID NO: 86 439 as MW at 47572.21cD

NOV2la, MAGPWTFTLLCGLLAATLIQATLSPTAVLILGPKVIKEKLTQELKDHNATSILQQLPL

CGS9446-O1 LS'~MREKPAGGIPVLGSLVNTVLKHIIWLKVITANILQLQVKPSANDQELLVKIPLDM
PrOteln Sequence VAGFNTPLVKTIVEFHMTTEAQATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLS

FLVNALAKQVMNLLVPSLPNLVKNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEF

DLLYPAIKGDTIQLYLGAKLLDSQGKVTKWFNNSAASLTMPTLDNIPFSLIVSHPFSL

IVSQDWKAAVAAVLSPEEFMVLLDSVLPESAHRLKSSIGLINEKEASSEAQFYTKGD

QLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITEIIHSILLPNQNGKLRSGVPVSLV

KALGFEAAESSLTKDALVLTPASLWKPSSPVSQ

SEQ ID NO: 87 1392 by NOV2lb, AAGCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACAC

DNA

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC
SeClueriCO

CTGAAACACATCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA

AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG

ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA

GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT

GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT

GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCGTCCCTGCCCAATCTAGTG

AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCTCC

TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCTGGAGTTTGACCTTCT

GTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC

TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA

CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT

GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG

AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC

TGGGACCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCGAGTTTTTTATAGA

CCAAGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGAA

GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA

CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT

GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG

ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG

TGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGC

CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG

ORF Start: AAG at ORF
1 Stop:
LV
at SEQ ID NO: 88 464 MW at 50459.SkD
as NOV2lb, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV

174308261 L~IIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ
PrOtelri SeClueriCe ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV

KNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEFDLLYPAIKGDTIQLYLGAKLLD

SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVLPE

SAHRLKSSIGLINEKAADKLGPTQIVKILTQDTPEFFIDQGHAKVAQLIVLEVFPSSE

ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITE

IIHSILLPNQNGKLRSGVPVSLVKALGFEAAESSLTKDALVLTPASLWKPSSPVSQLE

SEQ ID NO: 89 1392 by NOV21C, AAGCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCCGACAC

DNA

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC
SeClueriCe CTGAAGCACATCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA

AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG

ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA

GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT

GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT

GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG

AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCTCC

TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCTGGAGTTTGACCTTCT

GTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC

TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA

CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT

GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG

AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC

TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCGAGTTTTTTATAGA

CCAAGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGAA

GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA

CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT

GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG
ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG
TGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGC
CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG
ORF Start: AAG at 1 ORF
Stop:

SEQ ID NO: 90 464 as MW at 50433.4kD

NOV2IC, KLPTAVLILGPKVIKEKPTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV

I743OH266 PrOtelri L~IIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ

S8C111eriCe ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV

KNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEFDLLYPAIKGDTIQLYLGAKLLD

SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVLPE

SAHRLKSSIGLINEKAADKLGSTQIVKILTQDTPEFFIDQGHAKVAQLIVLEVFPSSE

ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITE

IIHSILLPNQNGKLRSGVPVSLVKALGFEAAESSLTKDALVLTPASLWKPSSPVSQLE

SEQ ID NO: 91 1392 by NOV2Id, AAGCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACAC

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC
SeCILIeriCB

CTGAAGCACATCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA

AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG

ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA

GCCACCATCCACATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT

GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT

GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG

AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCTCC

TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCTGGAGTTTGACCTTCT

GTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC

TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA

CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT

GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG

AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC

TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCGAGTTTTTTATAGA

CCAAGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGAA

GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA

CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT

GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG

ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG

TGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGC

CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG

ORF Start: AAG at 1 ORF
Stop:

SEQ ID NO: 92 464 MW at 50430.4kD
as NOV2ld, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV

I743OH27H PrOtelri L~IIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ

Se lleriCe ATIHMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV

KNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEFDLLYPAIKGDTIQLYLGAKLLD

SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVLPE

SAHRLKSSIGLINEKAADKLGSTQIVKILTQDTPEFFIDQGHAKVAQLIVLEVFPSSE

ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITE

IIHSILLPNQNGKLRSGVPVSLVKALGFEAAESSLTKDALVLTPASLWKPSSPVSQLE

SEQ ID NO: 93 1392 by NOV2le, AAGCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACAC

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC
SCqLleriCe CTGAAGCACATCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA
AGCCCTCGGCCAATGACCAGGAGCTGCTAGTTAAGATCCCCCTGGACATGGTGGCTGG

ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA

GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT

GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT

GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG

AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCTCC

TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCTGGAGTTTGACCTTCT

GTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC

TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA

CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT

GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG

AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC

TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCGAGTTTTTTATAGA

CCAAGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGAA

GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA

CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCCCTGATCGGATCCAGCT

GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG

ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG

CGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGC

CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG

ORF Start: AAG at ORF
1 Stop:

SEQ ID NO: 94 464 MW at 50431.4kD
as NOV218, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV

1743OH2H3 L~IIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ
PrOt8lri SeClliCriCB ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV

KNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEFDLLYPAIKGDTIQLYLGAKLLD

SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVLPE

SAHRLKSSIGLINEKAADKLGSTQIVKILTQDTPEFFIDQGHAKVAQLIVLEVFPSSE

ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISPDRIQLMNSGIGWFQPDVLKNIITE

IIHSILLPNQNGKLRSGVPASLVKALGFEAAESSLTKDALVLTPASLWKPSSPVSQLE

SEQ ID NO: 95 1392 by NOV2lf, AAGCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACAC

DNA

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC
SCC]lleriCC

CTGAAGCACATCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA

AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG

ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA

GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT

GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT

GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG

AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCTCC

TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCTGGAGTTTGACCTTCT

GTATCCTGCCATCAAGGGTGACACCGTTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC

TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA

CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT

GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG

AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC

TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCGAGTTTTTTATAGA

CCAGGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGAA

GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA

CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT

GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG

ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG

TGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGC

CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG

ORF Start: AAG at 1 ORF Stop:
SEQ ID NO: 96 464 as ~~~.~~r~ ~MW at 50435.4kD

NOV2lf, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV

174308287 L~IIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ
PrOtelri Se L12riC2 ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV

KNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEFDLLYPAIKGDTVQLYLGAKLLD

SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVLPE

SAHRLKSSIGLINEKAADKLGSTQIVKILTQDTPEFFIDQGHAKVAQLIVLEVFPSSE

AI~RPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITE

IIHSILLPNQNGKLRSGVPVSLVKALGFEAAESSLTKDALVLTPASLWKPSSPVSQLE

SEQ ID NO: 97 1392 by NOV2lg, ~GCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACAC

DNA

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC
SeCllleriCe CTGAAGCACATCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA

AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG

ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA

GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT

GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT

GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG

AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCTCC

TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCTGGAGTTTGACCTTCT

GTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC

TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA

CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT

GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG

AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC

TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCGAGTTTTTTATAGA

CCAAGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGAA

GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA

CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT

GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG

ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAGATTAAGATCTGGGGTCCCAG

TGTCATTGGTGAAGGCCTTGGGATTTGAGGCAGCTGAGTCCTCACTGACCAAGGATGC

CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG

ORF Start: AAG at ORF
1 Stop:

SEQ ID NO: 98 464 MW at 50477.5kD
as NOV2lg, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV

1743O8293 L~IIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ
PrOtelri Se ileriCe ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV

KNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEFDLLYPAIKGDTIQLYLGAKLLD

SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVI~PE

SAHRLKSSIGLINEKAADKLGSTQIVKILTQDTPEFFIDQGHAKVAQLIVLEVFPSSE

ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITE

IIHSILLPNQNGRLRSGVPVSLVKAI~GFEAAESSLTKDALVLTPASLWKPSSPVSQLE

SEQ ID NO: 99 1392 by NOV2111, ~GCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACAC

DNA

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC
SeCltleriCe CTGAAGCACGTCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA

AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG

ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA

GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT

GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT

GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG

AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCTCC

TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCTGGAGTTTGACCTTCT

GTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC

TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA

CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT

GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG

AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC

TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCAAGTTTTTTATAGA

CCAAGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGAA

GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA

CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT

GATGAACGCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG

ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG

TGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGC

CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG

ORF Start: AAG at ORF
1 Stop:

SEQ ID NO: 100 464 MW at 50418.SkD
as NOV2111, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV

1743Og3O1 L~VIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ
PIOtelri Se ileriCe ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV

KNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEFDLLYPAIKGDTIQLYLGAKLLD

SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVLPE

SAHRLKSSIGLINEKAADKLGSTQIVKILTQDTPKFFIDQGHAKVAQLIVLEVFPSSE

ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNAGIGWFQPDVLKNIITE

IIHSILLPNQNGKLRSGVPVSLVKALGFEAAESSLTKDALVLTPASLWKPSSPVSQLE

SEQ ID NO: 101 1392 by NOV211, AAGCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACAC

DNA

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCCGGTGAACACCGTC
Sequence CTGAAGCACGTCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA

AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG

ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA

GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT

GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT

GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG

AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCTCC

TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGGCCGTCTGGAGTTTGACCTTCT

GTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC

TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA

CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT

GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG

AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC

TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCAAGTTTTTTATAGA

CCAAGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGAA

GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA

CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT

GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG

ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG

TGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGC

CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG

ORF Start: AAG at ORF
1 Stop:

SEQ ID NO: 102 464 MW at 50360.4kD
as NOV211, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSPVNTV

1743O8311 L~VIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ
PIOtelri SeqlleriCe ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV

KNQLCPVIEASFNGMYADLLQLVKVPISLSIGRLEFDLLYPAIKGDTIQLYLGAKLLD

SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVLPE

SAHRLKSSIGLINEKAADKLGSTQIVKILTQDTPKFFIDQGHAKVAQLIVLEVFPSSE

ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITE

IIHSILLPNQNGKLRSGVPVSLVKALGFEAAESSLTKDALVLTPASLWKPSSPVSQLE

SEQ ID NO: 103 1392 by NOV21J, ~GCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACAC

DNA

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC
SeqlleriCO

CTGAAGCACATCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA

AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG

ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA

GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT

GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT

GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG

AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCTCC

TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCTGGAGTTTGACCTTCT

GTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC

TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA

CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT

GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG

AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC

TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCGAGTTTTTTATAGA

CCAAGGCCATGCCAGGGTGGCCCAACTGATCGTGCTGGAAGTGTCTCCCTCCAGTGAA

GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA

CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT

GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG

ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG

TGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGATGAGTCCTCACTGACCAAGGATGC

CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG

ORF Start: AAG at ORF Stop:

SEQ ID NO: 104 464 as MW at 50461.4kD

NOV2lj, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV

1743OH31S L~IIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ
PIOtClri S2 LleriCe ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV

KNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEFDLLYPAIKGDTIQLYLGAKLLD

SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVLPE

SAHRLKSSIGLINEKAADKLGSTQIVKILTQDTPEFFIDQGHARVAQLIVLEVSPSSE

ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITE

IIHSILLPNQNGKLRSGVPVSLVKALGFEADESSLTKDALVLTPASLWKPSSPVSQLE

SEQ ID NO: lOS 1392 by NOV21IC, AAGCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACAC

DNA

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC
S2ClileriCe CTGAAGCACATCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA

AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG

ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA

GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT

GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT

GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG

AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCTCC

TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCTGGAGTTTGACCTTCT

GTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC

TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA

CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT

GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG

AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC

TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCGAGTTTTTTATAGA

CCAAGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGTA

GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA

CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT

GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG

ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG' TGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGC' CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG' Start: AAG at 1 ~ORF Stop:
SEQ ID NO: 106 464 as !MW at 50419.SkD
NOV211C, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV', 174308321 L~IIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ'', PrOtelri SeClLleriC2 ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV', ' KNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEFDLLYPAIKGDTIQLYLGAKLLD
, SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVI~PE', SAHRLKSSIGLINEKAADKLGSTQIVKILTQDTPEFFIDQGHAKVAQLIVLEVFPSSV'', ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITE', IIHSILLPNQNGKLRSGVPVSLVKALGFEAAESSLTKDALVI~TPASLWKPSSPVSQLE', SEQ ID NO: 107 ( 1392 by NOV211, ~~GCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACAC
174308327 DNA AGGAGCTGAAGGACCACAACGCCACCAGCATCCTGCAGCAGCTGCCGCTGCTCAGTGC', CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC', SeCllleriCe CTGAAGCACATCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA', AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG'' ATTCAACACGCCCCTGGTCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAA', GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT', GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT'', GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG~, AAAAACCAGCTGTGTCCCGTGATCGAGGCTTCCTTCAATGGCATGTATGCAGACCCCC~I
GTATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGACI
TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA', CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT', GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG', AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC', TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACGCTCCCGAGTTTTTTATAGA'' CCAAGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGAA', GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA', CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT', GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG', ATCATCCACTCCATCCTGCTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG' TGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGC' CCTTGTGCTTACTCCAGCCTCCTTGTGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG' ORF Start: AAG at 1 ORF Stop:
SEQ ID NO: 108 464 as MW at 50403.4kD
NOV211, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV', '174308327 PrOtelri L~IIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLVKTIVEFHMTTEAQ', 'S8 ileriCB ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV'', KNQLCPVIEASFNGMYADPLQLVKVPISLSIDRLEFDLLYPAIKGDTIQLYLGAKLLD''~
' SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVLPE'I
SAHRLKSSIGLINEKAADKLGSTQIVKILTQDAPEFFIDQGHAKVAQLIVLEVFPSSE'~
ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITEIi IIHSILLPNQNGKLRSGVPVSLVKALGFEAAESSLTKDALVLTPASLWKPSSPVSQLE~I
SEQ ID NO: 109 ~ 1392 by NOV21ri1, ~GCTTCCCACTGCAGTTCTCATCCTCGGCCCAAAAGTCATCAAAGAAAAGCTGACACI

CATGCGGGAAAAGCCAGCCGGAGGCATCCCTGTGCTGGGCAGCCTGGTGAACACCGTC~I
S2C1L1eriCe CTGAAGCACGTCATCTGGCTGAAGGTCATCACAGCTAACATCCTCCAGCTGCAGGTGA'', AGCCCTCGGCCAATGACCAGGAGCTGCTAGTCAAGATCCCCCTGGACATGGTGGCTGG~I
ATTCAACACGCCCCTGGCCAAGACCATCGTGGAGTTCCACATGACGACTGAGGCCCAAI

GCCACCATCCGCATGGACACCAGTGCAAGTGGCCCCACCCGCCTGGTCCTCAGTGACT
GTGCCACCAGCCATGGGAGCCTGCGCATCCAACTGCTGCATAAGCTCTCCTTCCTGGT
GAACGCCTTAGCTAAGCAGGTCATGAACCTCCTAGTGCCATCCCTGCCCAATCTAGTG
TGCAGCTGGTGAAGGTGCCCATTTCCCTCAGCATTGACCGTCTGGAGTTTGACCTTCT
GCATCCTGCCATCAAGGGTGACACCATTCAGCTCTACCTGGGGGCCAAGTTGTTGGAC
TCACAGGGAAAGGTGACCAAGTGGTTCAATAACTCTGCAGCTTCCCTGACAATGCCCA
CCCTGGACAACATCCCGTTCAGCCTCATCGTGAGTCAGGACGTGGTGAAAGCTGCAGT
GGCTGCTGTGCTCTCTCCAGAAGAATTCATGGTCCTGTTGGACTCTGTGCTTCCTGAG
AGTGCCCATCGGCTGAAGTCAAGCATCGGGCTGATCAATGAAAAGGCTGCAGATAAGC
TGGGATCTACCCAGATCGTGAAGATCCTAACTCAGGACACTCCCAAGTTTTTTATAGA
CCAAGGCCATGCCAAGGTGGCCCAACTGATCGTGCTGGAAGTGTTTCCCTCCAGTGAA
GCCCTCCGCCCTTTGTTCACCCTGGGCATCGAAGCCAGCTCGGAAGCTCAGTTTTACA
CCAAAGGTGACCAACTTATACTCAACTTGAATAACATCAGCTCTGATCGGATCCAGCT
GATGAACTCTGGGATTGGCTGGTTCCAACCTGATGTTCTGAAAAACATCATCACTGAG
ATCATCCACTCCATCCTACTGCCGAACCAGAATGGCAAATTAAGATCTGGGGTCCCAG
TGTCATTGGTGAAGGCCTTGGGATTCGAGGCAGCTGAGTCCTCACTGACCAAGGATGC
CCTTGTGCTTACTCCAGCCTCCTTGGGGAAACCCAGCTCTCCTGTCTCCCAGCTCGAG
ORF Start ~AAG at ORF
1 ' Stop:

SEQ ID NO: 110 ' 464 MW at S02S1.2kD
as NOV21II1, KLPTAVLILGPKVIKEKLTQELKDHNATSILQQLPLLSAMREKPAGGIPVLGSLVNTV

1743OH337 L~VIWLKVITANILQLQVKPSANDQELLVKIPLDMVAGFNTPLAKTIVEFHMTTEAQ
PIOtelri S8 L1e11Ce ATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLSFLVNALAKQVMNLLVPSLPNLV

KNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEFDLLHPAIKGDTIQLYLGAKLLD

SQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWKAAVAAVLSPEEFMVLLDSVLPE

SAHRLKSSIGLINEKAADKLGSTQIVKILTQDTPKFFIDQGHAKVAQLIVLEVFPSSE

ALRPLFTLGIEASSEAQFYTKGDQLILNLNNISSDRIQLMNSGIGWFQPDVLKNIITE

IIHSILLPNQNGKLRSGVPVSLVKALGFEAAESSLTKDALVLTPASLGKPSSPVSQLE

SEQ ID NO: 111 1023 by NOV2lri, CCTCTGACACCTGGGAAGATGGCCGGCCCGTGGACCTTCACCCTTCTCTGTGGTTTGC

DNA

AAAAGTCATCAAAGAAAAGCTGACACAGGAGCTGAAGGACCACAACGCCACCAGCATC
S8ql12riC8 CTGCAGCAGCTGCCGCTGCTCAGTGCCATGCGGGAAAAGCCAGCCGGAGGCATCCCTG

TGCTGGGCAGCCTGGTGAACACCGTCCTGAAGCACGTCATCTGGCTGAAGGTCATCAC

AGCTAACATCCTCCAGCTGCAGGTGAAGCCCTCGGCCAATGACCAGGAGCTGCTAGTC

AAGATCCCCCTGGACATGGTGGCTGGATTCAACACGCCCCTGGTCAAGACCATCGTGG

AGTTCCACATGACGACTGAGGCCCAAGCCACCATCCGCATGGACACCAGTGCAAGTGG

CCCCACCCGCCTGGTCCTCAGTGACTGTGCCACCAGCCATGGGAGCCTGCGCATCCAA

CTGCTGCATAAGCTCTCCTTCCTGGTGAACGCCTTAGCTAAGCAGGTCATGAACCTCC

TAGTGCCATCCCTGCCCAATCTAGTGAAAAACCAGCTGTGTCCCGTGATCGAGGCTTC

CTTCAATGGCATGTATGCAGACCTCCTGCAGCTGGTGAAGGTGCCCATTTCCCTCAGC

ATTGACCGTCTGGAGTTTGACCTTCTGTATCCTGCCATCAAGGGTGACACCATTCAGC

TCTACCTGGGGGCCAAGTTGTTGGACTCACAGGGAAAGGTGACCAAGTGGTTCAATAA

CTCTGCAGCTTCCCTGACAATGCCCACCCTGGACAACATCCCGTTCAGCCTCATCGTG

AGTCAGGACGTGGTGAAAGCTGCAGTGGCTGCTGTGCTCTCTCCAGAAGAATTCATGG

TCCTGTTGGACTCTGTGGTAAACCTCAGCACAAGGCAGAGAATAGGGCCGCCCAGGCC

ACATCATAGGAATTTCCTGAACACAGGGTGCCCCTAA

ORF Start: ATG at ORF
19 Stop:
TAA
at SEQ ID NO: 112 334 MW at 36309.SkD
as NOV2111, MAGPWTFTLLCGLLAATLIQATLSPTAVLILGPKVIKEKLTQELKDHNATSILQQLPL

P1'Otelri SeC111e11Ce VAGFNTPLVKTIVEFHMTTEAQATIRMDTSASGPTRLVLSDCATSHGSLRIQLLHKLS

FLVNALAKQVMNLLVPSLPNLVKNQLCPVIEASFNGMYADLLQLVKVPISLSIDRLEF

DLLYPAIKGDTIQLYLGAKLLDSQGKVTKWFNNSAASLTMPTLDNIPFSLIVSQDWK

AAVAAVLSPEEFMVLLDSVVNLSTRQRIGPPRPHHRNFLNTGCP

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 21B.
Table 21B. Comparison of NOV2la against NOV2lb through NOV2ln.
NOV2la Residues/Identities/

Protein SequenceMatch ResiduesSimilarities for the Matched Region NOV2lb 25..439 388/472 (82%) 3..462 393/472 (83%) NOV2lc 25..439 405/468 (86%) 3..462 405/468 (86%) NOV21 d 25..439 405/468 (86%) 3..462 405/468 (86%) NOV2le 25..439 404/468 (86%) 3..462 404/468 (86%) NOV2lf 25..439 405/468 (86%) 3..462 406/468 (86%) NOV21 g 25..439 405/468 (86%) 3..462 406/468 (86%) NOV2lh 25..439 404/468 (86%) 3..462 406/468 (86%) NOV2li 25..439 403/468 (86%) 3..462 404/468 (86%) NOV21 j 25..439 405/468 (86%) 3..462 405/468 (86%) NOV2lk 25..439 406/468 (86%) 3..462 406/468 (86%) NOV211 25..439 405/468 (86%) 3..462 405/468 (86%) NOV2lm 25..439 402/468 (85%) 3..462 404/468 (85%) NOV2ln 1..318 308/318 (96%) 1..310 310/318 (96%) Further analysis of the NOV2la protein yielded the following properties shown in Table 21C.
Table 21C. Protein Sequence Properties NOV2la PSort 0.6138 probability located in outside; 0.4772 probability located in lysosome analysis: (lumen); 0.1000 probability located in endoplasmic reticulum (membrane);
0.1000 probability located in endoplasmic reticulum (lumen) SignalP ~ Likely cleavage site between residues 25 and 26 analysis:
A search of the NOV2la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 21D.
Table 21D. Geneseq Results for NOV2la NOV2la Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value ResiduesRegion AAY77126 Human neurotransmission-associated1..439 431/492 (87%)0.0 protein (NTAP) 2799056 1..484 431/492 (87%) - Homo Sapiens, 484 aa. [W0200001821-A2, 13-JAN-2000]

AAG63976 Amino acid sequence of 1..439 430/492 (87%)0.0 a human Lng103 polypeptide - Homo1..484 431/492 (87%) Sapiens, 484 aa. [W0200161055-A2, 2001 ]

AAU29163 Human PRO polypeptide 1..439 430/492 (87%)0.0 sequence #140 - Homo Sapiens, 484 1..484 431/492 (87%) aa.

[W0200168848-A2, 20-SEP-2001 ]

AAB87564 Human PR01357 - Homo sapiens,1..439 430/492 (87%)0.0 484 aa. [W0200116318-A2, 1..484 431/492 (87%) MAR-2001 ]

AAB66124 Protein of the invention 1..439 430/492 (87%)0.0 #36 -Unidentified, 484 aa. 1..484 431/492 (87%) [W0200078961-A1, 28-DEC-2000]

In a BLAST search of public sequence databases, the NOV21 a protein was found to have homology to the proteins shown in the BLASTP data in Table 21E.
Table 21E. Public BLASTP Results for NOV2la NOV2la Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched Value Number ResiduesPortion Q96HK6 SIMILAR TO DNA SEGMENT, CHR 1..439 428/492 (86%) 0.0 2, MASSACHUSETTS INSTITUTE 1..484 431/492 (86%) OF TECHNOLOGY 19 - Homo sapiens (Human), 484 aa.
Q6l 114 e-127 GLAND PROTEIN - Mus musculus 1..473 324/482 (66%) (Mouse), 474 aa.

Q9BWZ6 DJ1187J4.1.1 (NOVEL PROTEIN 200..439 232/293 e-116 (79%) SIMILAR TO MOUSE VON EBNER 1..285 232/293 (79%) SALIVARY GLAND PROTEIN, ISOFORM 1.) - Homo Sapiens (Human), 285 as (fragment).

Q9BQP8 BA49G10.6 (SIMILAR TO MUR1NE 1..199 199/199 e-107 (100%) VON EBNER MINOR SALIVARY 1..199 199/199 (100%) GLAND PROTEIN, ISOFORM 1 ) -Homo Sapiens (Human), 199 as (fragment).

Q9H4V6 DJ1187J4.1.2 (NOVEL PROTEIN 272..439 160/221 1e-73 (72%) SIMILAR TO MOUSE VON EBNER 1..213 160/221 (72%) SALIVARY GLAND PROTEIN, ISOFORM 2.) - Homo sapiens (Human), 213 aa.

PFam analysis predicts that the NOV2la protein contains the domains shown in the Table 21F.
Table 21F.
Domain Analysis of NOV2la Identities/

Pfam DomainNOV2la Match RegionSimilarities Expect Value for the Matched Region No Significant Matches Found EXrIIVIP1,E 22.
The NOV22 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 22A.
Table 22A. NOV22 Sequence Analysis SEQ ID NO: 113 2020 by NOV22a, CATGAGTGAATGAAGGCACATGACAAACCTCCAGACCTGTGGAGACTGAAGGCTGAGA

DNA

GCTGCAAGAGGCCTACGTGCGGGTGGTCACCGAGAAGTCCCCGACCGACTGGGCTCTC
Sequence TTTACCTATGAAGGCAACAGCAATGACATCCGCGTGGCTGGCACAGGGGAGGGTGGCC

TGGAGGAGATGGTGGAGGAGCTCAACAGCGGGAAGGTGATGTACGCCTTCTGCAGAGT

GAAGGACCCCAACTCTGGACTGCCCAAATTTGTCCTCATCAACTGGACAGGCGAGGGC

GTGAACGATGTGCGGAAGGGAGCCTGTGCCAGCCACGTCAGCACCATGGCCAGCTTCC

TGAAGGGGGCCCATGTGACCATCAACGCACGGGCCGAGGAGGATGTGGAGCCTGAGTG

CATCATGGAGAAGGTGGCCAAGGCTTCAGGTGCCAACTACAGCTTTCACAAGGAGAGT

GGCCGCTTCCAGGACGTGGGACCCCAGGCCCCAGTGGTGAGTGGCTCTGTGTACCAGA

AGACCAATGCCGTGTCTGAGATTAAAAGGGTTGGTAAAGACAGCTTCTGGGCCAAAGC

AGAGGACCCTGAGACCTTGTCAGAAAGAAATAAAAGAGAAAGAGAGGAGGAGGCACAG

CGGCAGCTGGAGCAGGAGCGCCGGGAGCGTGAGCTGCGTGAGGCTGCACGCCGAGAGC

AGCGCTATCAGGAGCAGAGGTGGCGAGGCCAGAGCAGGACGTGGGAGCAGCAGCAAGA

AGTGGTTTCAAGGAACCGAAATGAGCAGGGGTCAACATGTGCTTCCCTCCAGGAGTCT

GCCGTGCACCCGAGGGAGATTTTCAAGCAGAAGGAGAGGGCCATGTCCACCACCTCCA

TCTCCAGTCCTCAGCCTGGCAAGCTGAGGAGCCCCTTCCTGCAGAAGCAGCTCACCCA

ACCAGAGACCCACTTTGGCAGAGAGCCAGCTGCTGCCATCTCAAGGCCCAGGGCAGAT

CTCCCTGCTGAGGAGCCGGCGCCCAGCACTCCTCCATGTCTGGTGCAGGCAGAAGAGG

AGGCTGTGTATGAGGAACCTCCAGAGCAGGAGACCTTCTACGAGCAGCCCCCACTGGT

GCAGCAGCAAGGTGCTGGCTCTGAGCACATTGACCACCACATTCAGGGCCAGGGGCTC

AGTGGGCAAGGGCTCTGTGCCCGTGCCCTGTACGACTACCAGGCAGCCGACGACACAG

AGATCTCCTTTGACCCCGAGAACCTCATCACGGGCATCGAGGTGATCGACGAAGGCTG

GTGGCGTGGCTATGGGCCGGATGGCCATTTTGCATGTTCCCTGCCAACTACGTGGAGC

TCATTGAGTGAGGCTGAGGGCACATCTTGCCCTTCCCCTCTCAGACATGGCTTCCTTA

TTGCTGGAAGAGGAGGCCTGGGAGTTGACATTCAGCACTCTTCCAGGAATAGGACCCC

CAGTGAGGATGAGGCCTCAGGGCTCCCTCCGGCTTGGCAGACTCAGCCTGTCACCCCA

AATGCAGCAATGGCCTGGTGATTCCCACACATCCTTCCTGCATCCCCCGACCCTCCCA

GACAGCTTGGCTCTTGCCCCTGACAGGATACTGAGCCAAGCCCTGCCTGTGGCCAAGC

CCTGAGTGGCCACTGCCAAGCTGCGGGGAAGGGTCCTGAGCAGGGGCATCTGGGAGGC

TCTGGCTGCCTTCTGCATTTATTTGCCTTTTTTCTTTTTCTCTTGCTTCTAAGGGGTG

GTGGCCACCACTGTTTAGAATGACCCTTGGGAACAGTGAACGTAGAGAATNGTTTTTA

GCAGAGTTGTGACCAAAGTCAGAGTGGATCATGGTGGTTTGGCAGCAGGGAATCTGTC

TTGTTGGAGCCTGCTCTGTGCTCCCCACTCCATTTCTCTGTCCCTCTGCCTGGGCTAT

GGGAAGTGGGGATGCAGATGGCAAGCTCCCACCCTGGGTATTCAAAAA

O1RF Start: ATG at IO OItF Stop: TGA at 1585 SEQ ID NO: 114 525 as MW at 58507.21cD

NOV22a, MKAHDKPPDLWRLKAESLYRCCGAEEFANYSRSCPALQEAYVRVVTEKSPTDWALFTY

PTOtelri SequeriCe WKGACASHVSTMASFLKGAHVTINARAEEDVEPECIMEKVAKASGANYSFHKESGRF

QDVGPQAPWSGSVYQKTNAVSEIKRVGKDSFWAKAEDPETLSERNKREREEEAQRQL

EQERRERELREAARREQRYQEQRWRGQSRTWEQQQEWSRNRNEQGSTCASLQESAVH

PREIFKQKERAMSTTSISSPQPGKLRSPFLQKQLTQPETHFGREPAAAISRPRADLPA

EEPAPSTPPCLVQAEEEAWEEPPEQETFYEQPPLVQQQGAGSEHIDHHIQGQGLSGQ

GLCARALYDYQAADDTEISFDPENLITGIEVIDEGWWRGYGPDGHFACSLPTTWSSLS

EAEGTSCPSPLRHGFLIAGRGGLGVDIQHSSRNRTPSEDEASGLPPAWQTQPVTPNAA

MAW

Further analysis of the NOV22a protein yielded the following properties shown in Table 22B.
Table 22B. Protein Sequence Properties NOV22a PSort 0.6500 probability located in cytoplasm; 0.1000 probability located in analysis: mitochondrial matrix space; 0.1000 probability located in lysosome (lumen);
0.0000 probability located in endoplasmic reticulum (membrane) SignalP No Known Signal Sequence Predicted analysis:
A search of the NOV22a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 22C.
Table 22C. Geneseq Results for NOV22a NOV22a Identities/
Geneseq Protein/Organism/Length [Patent #, Expect Identifier Date] Residues/ Similarities for Value ResiduesRegion AAB93895 Human protein sequence 28..465 407/440 (92%)0.0 SEQ ID

N0:13840 - Homo Sapiens, 3..439 411/440 (92%) 439 aa.

[EP 1074617-A2, 07-FEB-2001 ]

AAY85662 Human tyrosine kinase 28..465 399/440 (90%)0.0 substrate tks 118/Dresh protein 3..431 403/440 (90%) sequence -Homo Sapiens, 431 aa.

[W0200061750-A2, 19-OCT-2000]

AAB20896 Human dreblin-like protein28..465 398/440 (90%)0.0 and SH3 domain sequence SEQ ID 3..431 403/440 (91%) NO:1 -Homo sapiens, 431 aa.

[JP2000197489-A, 18-JUL-2000]

AAM79569 Human protein SEQ ID NO 28..465 397/439 (90%)0.0 Homo sapiens, 458 aa. 31..458 401/439 (90%) [W0200157190-A2, 09-AUG-2001]

AAM78585 Human protein SEQ ID NO 28..465 397/439 (90%)0.0 Homo Sapiens, 430 aa. 3..430 401/439 (90%) [W0200157190-A2, 09-AUG-2001]

In a BLAST search of public sequence databases, the NOV22a protein was found to have homology to the proteins shown in the BLASTP data in Table 22D.
Table 22D. Public BLASTP Results for NOV22a Protein NOV22a Identities/

AccessionProtein/Organism/Length Residues/SimilaritiesExpect for Number Match the MatchedValue ResiduesPortion Q96K74 CDNA FLJ14461 FIS, CLONE 28..465 407/440 0.0 (92%) MAMMA 1000173, HIGHLY SIMILAR3..439 411 /440 (92%) TO HOMO SAPIENS SRC

CONTAINING PROTEIN HIP-SS

MRNA - Homo Sapiens (Human), aa.

Q96F30 SIMILAR TO SRC HOMOLOGY 28..465 399/440 0.0 3 (90%) DOMAIN-CONTAINING PROTEIN 3..431 403/440 (90%) HIP-55 - Homo sapiens (Human), aa.

Q9UJU6 SRC HOMOLOGY 3 DOMAIN- 28..465 397/439 0.0 (90%) CONTAINING PROTEIN HIP-55 3..430 401/439 (90%) (DREBRIN F) - Homo Sapiens (Human), 430 aa.

Q9NR72 CERVICAL SH3P7 (MUCIN- 28..465 395/439 0.0 (89%) 3..430 401/439 (90%) Sapiens (Human), 430 aa.

Q62418 DREBR1N-LIKE SH3 DOMAIN- 29..465 345/439 0.0 (78%) CONTA>NING PROTEIN SH3P7 4..433 371/439 - Mus (83%) musculus (Mouse), 433 aa.

PFam analysis predicts that the NOV22a protein contains the domains shown in the Table 22E.
Table 22E. Domain Analysis of NOV22a Identities/

Pfam Domain NOV22a Match Similarities Expect Region for the Matched Value Region cofilin_ADF: domain 1 of 1 35..158 27/151 (18%) 7.8e-21 101/151 (67%) SH3: domain 1 of 1 408..455 16/58 (28%) 0.0038 31/58 (53%) Peptidase M36: domain 1 of 486..50911/24 (46%) 2.9 1 13/24 (54%) EXAMPLE 23.
The NOV23 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 23A.
Table 23A. NOV23 Sequence Analysis SEQ ID NO: 115 2898 by NOV23a, CTCTGGTCACAACTGCATCAATGACATGCAGAAAGCAGGTCAGGTCACAAGATGCAGC

DNA

GCCCTTCCCGAATCCATCCCATCAGCTCCTGGGACACTGCCTCATTTCATAGAGGAGC
Sequence CAGATGATGCTTATATTATCAAGAGCAACCCTATTGCACTCAGGTGCAAAGCGAGGCC

AGCCATGCAGATATTCTTCAAATGCAACGGCGAGTGGGTCCATCAGAACGAGCACGTC

TCTGAAGAGACTCTGGACGAGAGCTCAGGTTTGAAGGTCCGCGAAGTGTTCATCAATG

TTACTAGGCAACAGGTGGAGGACTTCCATGGGCCCGAGGACTATTGGTGCCAGTGTGT

GGCGTGGAGCCACCTGGGTACCTCCAAGAGCAGGAAGGCCTCTGTGCGCATAGCCTAT

TTACGGAAAAACTTTGAACAAGACCCACAAGGAAGGGAAGTTCCCATTGAAGGCATGA

TTGTACTGCACTGCCGCCCACCAGAGGGAGTCCCTGCTGCCGAGGTGGAATGGCTGAA

AAATGAAGAGCCCATTGACTCTGAACAAGACGAGAACATTGACACCAGGGCTGACCAT

AACCTGATCATCAGGCAGGCACGGCTCTCGGACTCAGGAAATTACACCTGCATGGCAG

CCAACATCGTGGCTAAGAGGAGAAGCCTGTCGGCCACTGTTGTGGTCTACGTGAATGG

AGGCTGGTCTTCCTGGACAGAGTGGTCAGCCTGCAATGTTCGCTGTGGTAGAGGATGG

CAGAAACGTTCCCGGACCTGCACCAACCCAGCTCCTCTCAATGGTGGGGCCTTTTGTG

AGGGAATGTCAGTGCAGAAAATAACCTGCACTTCTCTTTGTCCTGTGGATGGGAGCTG

GGAAGTGTGGAGCGAATGGTCCGTCTGCAGTCCAGAGTGTGAACATTTGCGGATCCGG

GAGTGCACAGCACCACCCCCGAGAAATGGGGGCAAATTCTGTGAAGGTCTAAGCCAGG

AATCTGAAAACTGCACAGATGGTCTTTGCATCCTAAACTCCACCACCATGCAGGAACC

CAAGGTGACTGCCCTTCAGACGCTATGCCAAATTGAGAATGCCAGCGACATTGCTTTG

TACTCGGGCTTGGGTGCTGCCGTCGTGGCCGTTGCAGTCCTGGTCATTGGTGTCACCC

TTTACAGACGGAGCCAGAGTGACTATGGCGTGGACGTCATTGACTCTTCTGCATTGAC

AGGTGGCTTCCAGACCTTCAACTTCAAAACAGTCCGTCAAGGGAACTCCCTGCTCCTG

AATTCTGCCATGCAGCCAGATCTGACAGTGAGCCGGACATACAGCGGACCCATCTGTC
TGCAGGACCCTCTGGACAAGGAGCTCATGACAGAGTCCTCACTCTTTAACCCTTTGTC
GGACATCAAAGTGAAAGTCCAGAGCTCGTTCATGGTTTCCCTGGGAGTGTCTGAGAGA
GCTGAGTACCACGGCAAGAATCATTCCAGGACTTTTCCCCATGGAAACAACCACAGCT
TTAGTACAATGCATCCCAGAAATAAAATGCCCTACATCCAAAATCTGTCATCACTCCC
CACAAGGACAGAACTGAGGACAACTGGTGTCTTTGGCCATTTAGGGGGGCGCTTAGTA
ATGCCAAATACAGGGGTGAGCTTACTCATACCACACGGTGCCATCCCAGAGGAGAATT
CTTGGGAGATTTATATGTCCATCAACCAAGGTGAACCCAGGTCAGATGGCTCTGAGGT
GCATTGACCATCCCGCACTGTGCAGATGTCAGTTCTGAGCATTGGAATATCCATTTAA
AGAAGAGGACACAGCAGGGCAAATGGGAGGAAGTGATGTCAGTGGAAGATGAATCTAC
ATCCTGTTACTGCCTTTTGGACCCCTTTGCGTGTCATGTGCTCCTGGACAGCTTTGGG
ACCTATGCGCTCACTGGAGAGCCAATCACAGACTGTGCCGTGAAGCAACTGAAGGTGG
CGGTTTTTGGCTGCATGTCCTGTAACTCCCTGGATTACAACTTGAGAGTTTACTGTGT
GGACAATACCCCTTGTGCATTTCAGGAAGTGGTTTCAGATGAAAGGCATCAAGGTGGA
CAGCTCCTGGAAGAACCAAAATTGCTGCATTTCAAAGGGAATACCTTTAGTCTTCAGA
TTTCTGTCCTTGATATTCCCCCATTCCTCTGGAGAATTAAACCATTCACTGCCTGCCA
GGAAGTCCCGTTCTCCCGCGTGTGGTGCAGTAACCGGCAGCCCCTGCACTGTGCCTTC
TCCCTGGAGCGTTATACGCCCACTACCACCCAGCTGTCCTGCAAAATCTGCATTCGGC
AGCTCAAAGGCCATGAACAGATCCTCCAAGTGCAGACATCAATCCTAGAGAGTGAACG
AGAAACCATCACTTTCTTCGCACAAGAGGACAGCACTTTCCCTGCACAGACTGGCCCC
AAAGCCTTCAAAATTCCCTACTCCATCAGACAGCGGATTTGTGCTACATTTGATACCC
CCAATGCCAAAGGCAAGGACTGGCAGATGTTAGCACAGAAAAACAGCATCAACAGGAG
GAATTTATCTTATTTCGCTACACAAAGTAGCCCATCTGCTGTCATTTTGAACCTGTGG
GAAGCTCGTCATCAGCATGATGGTGATCTTGACTCCCTGGCCTGTGCCCTTGAAGAGA
TTGGGAGGACACACACGAAACTCTCAAACATTTCAGAATCCCAGCTTGATGAAGCCGA
CTTCAACTACAGCAGGCAAAATGGACTCTAGTCCACTTCCTCCCATGAGACAGAGT
~~RF Start: ATG at 21 ORF Stop: TAG at 2871 ~1-S~'EQ ID NO: 116 950 as MW at 105960.6kD
'NOV23a, MTCRKQVRSQDAALSQTLFGELDLMAGTDNGEALPESIPSAPGTLPHFIEEPDDAYII

'CG59321-O1 KSNPIALRCKARPAMQIFFKCNGEWVHQNEHVSEETLDESSGLKVREVFINVTRQQVE'', PrOtelri ',SeCllleriCeDFHGPEDYWCQCVAWSHLGTSKSRKASVRIAYLRKNFEQDPQGREVPIEGMIVLHCRP', ' PEGVPAAEVEWLKNEEPIDSEQDENIDTRADHNLIIRQARLSDSGNYTCMAANIVAKR
, RSLSATVVVYVNGGWSSWTEWSACNVRCGRGWQKRSRTCTNPAPLNGGAFCEGMSVQK', ITCTSLCPVDGSWEVWSEWSVCSPECEHLRIRECTAPPPRNGGKFCEGLSQESENCTD', GLCILNSTTMQEPKVTALQTLCQIENASDIALYSGLGAAWAVAVLVIGVTLYRRSQS'', DYGVDVIDSSALTGGFQTFNFKTVRQGNSLLLNSAMQPDLTVSRTYSGPICLQDPLDK' ELMTESSLFNPLSDIKVKVQSSFMVSLGVSERAEYHGKNHSRTFPHGNNHSFSTMHPR

NKMPYIQNLSSLPTRTELRTTGVFGHLGGRLVMPNTGVSLLIPHGAIPEENSWEIYMS

INQGEPRSDGSEVLLSPEVTCGPPDMIVTTPFALTIPHCADVSSEHWNIHLKKRTQQG

KWEEVMSVEDESTSCYCLLDPFACHVLLDSFGTYALTGEPITDCAVKQLKVAVFGCMS

CNSLDYNLRWCVDNTPCAFQEWSDERHQGGQLLEEPKLLHFKGNTFSLQISVLDIP

PFLWRIKPFTACQEVPFSRVWCSNRQPLHCAFSLERYTPTTTQLSCKICIRQLKGHEQ

ILQVQTSILESERETITFFAQEDSTFPAQTGPKAFKIPYSIRQRICATFDTPNAKGKD

WQMLAQKNSINRRNLSYFATQSSPSAVILNLWEARHQHDGDLDSLACALEEIGRTHTK

LSNISESQLDEADFNYSRQNGL

SEQ ID NO: 117 X2181 by NOV23b, ~CGGCCAGTCAGAACAATCCTCCTGTTTTTAATGAATTGGGTTTACCATTGACAATGCT

TCAATGACATGCAGAAAGCAGGTCGCGCCGCTGGCTCCCGTGGCTGGGGCTGTGTTTC
SeCllleriCe TGGGCGGGAGGGAACGGGGGTGGCCCAAGGAACTGACAATGGCGAAGCCCTTCCCGAA
TCCATCCCATCAGCTCCTGGGACACTGCCTCATTTCATAGAGGAGCCAGATGATGCTT
ATATTATCAAGAGCAACCCTATTGCACTCAGGTGCAAAGCGAGGCCAGCCATGCAGAT
ATTCTTCAAATGCAACGGCGAGTGGGTCCATCAGAACGAGCACGTCTCTGAAGAGACT
CTGGACGAGAGCTCAGGTTTGAAGGTCCGCGAAGTGTTCATCAATGTTACTAGGCAAC
AGGTGGAGGACTTCCATGGGCCCGAGGACTATTGGTGCCAGTGTGTGGCGTGGAGCCA
CCTGGGTACCTCCAAGAGCAGGAAGGCCTCTGTGCGCATAGCCTATTTACGGAAAAAC
TTTGAACAAGACCCACAAGGAAGGGAAGTTCCCATTGAAGGCATGATTGTACTGCACT

GCCGCCCACCAGAGGGAGTCCCTGCTGCCGAGGTGGAATGGCTGAAAAATGAAGAGCC

CATTGACTCTGAACAAGACGAGAACATTGACACCAGGGCTGACCATAACCTGATCATC

AGGCAGGCACGGCTCTCGGACTCAGGAAATTACACCTGCATGGCAGCCAACATCGTGG

CTAAGAGGAGAAGCCTGTCGGCCACTGTTGTGGTCTACGTGAATGGAGGCTGGTCTTC

CTGGACAGAGTGGTCAGCCTGCAATGTTCGCTGTGGTAGAGGATGGCAGAAACGTTCC

CGGACCTGCACCAACCCAGCTCCTCTCAATGGTGGGGCCTTTTGTGAGGGAATGTCAG

TGCAGAAAATAACCTGCACTTCTCTTTGTCCTGTGGATGGGAGCTGGGAAGTGTGGAG

CGAATGGTCCGTCTGCAGTCCAGAGTGTGAACATTTGCGGATCCGGGAGTGCACAGCA

CCACCCCCGAGAAATGGGGGCAAATTCTGTGAAGGTCTAAGCCAGGAATCTGAAAACT

GCACAGATGGTCTTTGCATCCTAGATAAAAAACCTCTTCATGAAATAAAACCCCAAAG

CATTGAGAATGCCAGCGACATTGCTTTGTACTCGGGCTTGGGTGCTGCCGTCGTGGCC

GTTGCAGTCCTGGTCATTGGTGTCACCCTTTACAGACGGAGCCAGAGTGACTATGGCG

TGGACGTCATTGACTCTTCTGCATTGACAGGTAACTCCCTGCTCCTGAATGCGAGCAC

ACTCCAGCCTCTGGAGAGACGACAACGCGTGAAGCAACTGAAGGTGGCGGGTTTTGGC

TGCATGTCCTGTAACTCCCTGGATTACAACTGGAGAGTTTACTGTGTGGACAAAACCC

CTTGGGCTTTTCAGGAAGTGGTTTCAGATGAAAGGCATCAAGGGGGACAGCTCCTGGA

AGAACCAAAATTGCTGCATTTCAAAGGGAATACCTTTAGTCTTCAGATTTCTGTCCTT

GATATTCCCCCATTCCTCTGGAGAATTAAACCATTCACTGCCTGCCAGGAAGTCCCGG

TCTCCCGCGTGTGGTGCAGTAACCGGCAGCCCCTGCACTGTGCCTTCTCCCTGGAGCG

TTATACGCCCACTACCACCCAGCTGTCCTGCAAAATCTGCATTCGGCAGCTCAAAGGC

CATGAACAGATCCTCCAAGTGCAGACATCAATCCTAGAGACTGGCCCCAAAGCCTTCA

AAATTCCCTACTCCATCAGACAGCGGATTTGTGCTACATTTGATACCCCCAATGCCAA

AGGCAAGGACTGGCAGATGTTAGCACAGAAAAACAGCATCAACAGGAATTTATCTTAT

TTCGCTACACAAAGTAGCCCATCTGCTGTCATTTTGAACCTGTGGGAAGCTCGTCATC

AGCATGATGGTGATCTTGACTCCCTGGCCTGTGCCCTTGAAGAGATTGGGAGGACACA

CACGAAACTCTCAAACATTTCAGAATCCCAGCTTGATGAAGCCGACTTCAACTACAGC

AGGCAAAATGGACTCTAGTCCACTTCCTCCCATGA

ORF Start: ATG at ORF
125 Stop:
TAG
at SEQ ID NO: 118 679 MW at 75724.81cD
as NOV23b, MQKAGRAAGSRGWGCVSGREGTGVAQGTDNGEALPESIPSAPGTLPHFIEEPDDAYII

PrOteln Sequence DFHGPEDYWCQCVAWSHLGTSKSRKASVRIAYLRKNFEQDPQGREVPIEGMIVLHCRP

PEGVPAAEVEWLKNEEPIDSEQDENIDTRADHNLIIRQARLSDSGNYTCMAANIVAKR

RSLSATVVVYVNGGWSSWTEWSACNVRCGRGWQKRSRTCTNPAPLNGGAFCEGMSVQK

ITCTSLCPVDGSWEVWSEWSVCSPECEHLRIRECTAPPPRNGGKFCEGLSQESENCTD

GLCILDKKPLHEIKPQSIENASDIALYSGLGAAWAVAVLVIGVTLYRRSQSDYGVDV

IDSSALTGNSLLLNASTLQPLERRQRVKQLKVAGFGCMSCNSLDYNWRVYCVDKTPWA

FQEWSDERHQGGQLLEEPKLLHFKGNTFSLQISVLDIPPFLWRIKPFTACQEVPVSR

VWCSNRQPLHCAFSLERYTPTTTQLSCKICIRQLKGHEQILQVQTSILETGPKAFKIP

YSIRQRICATFDTPNAKGKDWQMLAQKNSINRNLSYFATQSSPSAVILNLWEARHQHD

GDLDSLACALEEIGRTHTKLSNISESQLDEADFNYSRQNGL

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 23B.
Table 23B. Comparison of NOV23a against NOV23b and NOV23c.
Protein Sequence NOV23a Residues/ Identities/
Match Residues Similarities for the Matched Region NOV23b 27..444 357/419 (85%) 27..426 361/419 (85%) Further analysis of the NOV23a protein yielded the following properties shown in Table 23C.

Table 23C. Protein Sequence Properties NOV23a PSort 0.8411 probability located in mitochondrial inner membrane; 0.7000 probability analysis: located in plasma membrane; 0.3000 probability located in microbody (peroxisome); 0.2057 probability located in mitochondrial matrix space SignalP ~ No Known Signal Sequence Predicted analysis:
A search of the NOV23a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 23D.
Table 23D. Geneseq Results for NOV23a NOV23a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent for Identifier#, Date] Match the Matched Value Residues Region AAU12244 Human PR04326 polypeptide26..925 499/915 (54%)0.0 sequence - Homo Sapiens,26..933 651/915 (70%) 945 aa.

[W0200140466-A2, 07-JLJN-2001]

AAW78900 Rat UNC-5 homologue UNCSH-225..925 487/916 (53%)0.0 -Rattus sp, 943 aa. [W09837085-A1,23..931 648/916 (70%) 27-AUG-1998]

AAB50691 Human UNCSC protein SEQ 34..936 465/921 (50%)0.0 ID

N0:90 - Homo Sapiens, 49..930 621/921 (66%) 931 aa.

[W0200073328-A2, 07-DEC-2000]

AAW78898 Rat UNC-5 homologue UNCSH-126..936 417/921 (45%)0.0 -Rattus sp, 898 aa. [W09837085-A1,23..897 582/921 (62%) 27-AUG-1998]

AAM79128 Human protein SEQ ID 24..936 422/955 (44%)0.0 Homo Sapiens, 943 aa. 31..942 588/955 (61%) [W0200157190-A2, 09-AUG-2001]

In a B LAST search of public sequence databases, the NOV23a protein was found to have homology to the proteins shown in the BLASTP data in Table 23E.
Table 23E.
Public BLASTP
Results for NOV23a NOV23a Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched Value Number Residues Portion BAB83663 KIAA1777 PROTEIN (UNCSH4)27..950 906/926 (97%)0.0 -Homo Sapiens (Human), 30..948 910/926 (97%) 948 aa.

008722 TRANSMEMBRANE RECEPTOR 25..925488/916 (53%)0.0 UNCSH2 - Rarius norvegicus25..933649/916 (70%) (Rat), 945 aa.

Q9D398 6330415E02RIK PROTEIN - 1..925 491/940 (52%)0.0 Mus musculus (Mouse), 945 aa. 1..933 656/940 (69%) 008747 ROSTRAL CEREBELLAR 34..936468/921 (50%)0.0 MALFORMATION PROTEIN - 49..930622/921 (66%) Mus musculus (Mouse), 931 aa.

095185 TRANSMEMBRANE RECEPTOR 34..936465/921 (50%)0.0 UNCSC - Homo sapiens (Human),49..930621/921 (66%) 931 aa.

PFam analysis predicts that the NOV23a protein contains the domains shown in the Table 23F.
Table 23F. Domain Analysis of NOV23a Identities/

Pfam Domain NOV23a Match RegionSimilarities Expect Value for the Matched Region ig: domain 165..225 16/63 (25%) 5.2e-07 1 of 1 43/63 (68%) tsp-1: domain248..297 23/54 (43%) 1.6e-07 1 of 2 33/54 (61%) tsp-l: domain304..351 23/54 (43%) 0.0014 2 of 2 32/54 (59%) ZUS: domain 538..638 33/115 (29%) 7.8e-21 1 of 1 68/115 (59%) death: domain855..933 21/87 (24%) 4.4e-13 1 of 1 61/87 (70%) FXAMPI,F 24.
The NOV24 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 24A.
Table 24A. NOV24 Sequence Analysis SEQ ID NO: 119 898 by NOV24a, CCTGTGACTCCTCCATCCAGCTATGCCCCTGCTGCCCAGCACCGTGGGCCTGGCAGGC

CGS9S91-Ol CTGCTCTTCTGGGCTGGCCAGGCAGTGAACGCCTTGATAATGCCTAATGCTACCCCAG
DNA

CCCCGGCCCAGCCCGAGAGCACGGCTATGCGGCTCCTGAGTGGCCTGGAGGTGCCCAG
SeqlleriCe GTACCGCCGGAAGCGCCACATCTCTGTGAGAGACATGAATGCCTTACTGGATTATCAC

AACCACATCCGGGCCAGTGTGTACCCACCTGCCGCCAACATGGAATACATGGTGTGGG

ACAAGCGGCTGGCCAGGGCTGCCGAAGCCTGGGCCACCCAGTGCATCTGGGCACATGG

GCCTTCACAGCTGATGAGATACGTGGGCCAGAACCTCTCCATCCATTCTGGCCAGTAC

CGGTCCGTAGTGGATCTCATGAAGTCCTGGTCTGAGGAGAAGTGGCATTACTTGTTTC

CGGCCCCAAGGGACTGTAACCCACACTGCCCCTGGCGCTGCGATGGCCCCACCTGCTC

CCATTATACCCAGATGGTGTGGGCATCCTCCAATCGGCTGGGCTGTGCCATCCACACC

TGTAGTAGCATCAGTGTCTGGGGCAACACCTGGCATCGGGCGGCATACCTGGTCTGCA

ACTATGCCATTAAGGGCAACTGGATTGGCGAGTCCCCGTACAAGATGGGAAAGCCGTG

CTCCTCCTGTCCCCCCAGTTATCAAGGCAGCTGCAATAGCAACATGTGCTTCAAGGGG

CTGAAATCCAACAAGTTCACGTGGTTCTGAATTTTCTCTGGGCTTTGGTGCGCCTCCA

GCTGGGCCTGACCCTCCATGTCCTGCCCTCAAAAAACTGGGTGGAGAAATAATTGTTT

CTTTAAAGGATATGAGTTAGAATCACCC

ORF Start: ATG at ORF Stop:

at 782 SEQ ID NO: 120 253 as MW at 28604.6kD

NOV24a, MPLLPSTVGLAGLLFWAGQAVNALIMPNATPAPAQPESTAMRLLSGLEVPRYRRKRHI

CGS9S91-O1 S~DMNAI'LDYHNHIRASVYPPAANMEYMVWDKRLARAAEAWATQCIWAHGPSQLMRY

P1'Otelri SequeriCe VGQNLSIHSGQYRSWDLMKSWSEEKWHYLFPAPRDCNPHCPWRCDGPTCSHYTQMW

ASSNRLGCAIHTCSSISVWGNTWHRAAYLVCNYAIKGNWIGESPYKMGKPCSSCPPSY

QGSCNSNMCFKGLKSNKFTWF

Further analysis of the NOV24a protein yielded the following properties shown in Table 24B.
Table 24B.
Protein Sequence Properties NOV24a PSort 0.4400 probability located in lysosome (lumen); 0.3798 probability located in analysis:outside; 0.1000 probability located in endoplasmic reticulum (membrane);

0.1000 probability located in endoplasmic reticulum (lumen) SignalP Likely cleavage site between residues 24 and 2S

analysis:

A search of the NOV24a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 24C.
Table 24C. Geneseq Results for NOV24a E
NOV24a Identities/
eneseq Protein/Organism/Length Residues/j xpect [Patent Match SimilaritiesValue Identifier #, Date] Residuesfor r the Matched Region AAR79914 Trypsin inhibitory protein,57..253 130/197 (6S%)3e-86 isolated from human T98G cells - Homo 1..197 159/197 (79%) Sapiens, 198 aa. [JP07242700-A, SEP-1995]

AAR79915 Human trypsin inhibitory 67..253 125/187 (66%)1e-83 protein, residues 11-198 - Homo Sapiens, 1..187 152/187 (80%) aa. [JP07242700-A, 19-SEP-1995]

AAU290S8 Human PRO polypeptide 19..243 112/235 (47%)3e-70 sequence #3S - Homo Sapiens, 500 aa. 10..242 155/235 (6S%) [W0200168848-A2, 20-SEP-2001]

AAM41693 Human polypeptide SEQ 19..243 112/235 (47%)3e-70 93..325 155/235 (65%) [W0200153312-A1, 26-JUL-2001]

AAM39907 Human polypeptide SEQ 19..243 112/235 (47%)3e-70 - Homo Sapiens, 300 aa. 10..242 155/235 (65%) [W0200153312-Al, 26-JUL-2001]

In a BLAST search of public sequence databases, the NOV24a protein was found to have homology to the proteins shown in the BLASTP data in Table 24D.
Table 24D. Public BLASTP Results for NOV24a NOV24a Identities/

Protein Residues/ SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched ~ Value Number Residues Portion Q9H3Y0 DJ881L22.3 (NOVEL PROTEIN1..253 253/253 (100%)~ e-159 SIMILAR TO A TRYPS1N 1..253 253/253 (100%) .

, INHIBITOR) - Homo sapiens (Human), 253 aa.

043692 25 KDA TRYPS1N INHIBITOR37..253 137/217 (63%)6e-90 -Homo Sapiens (Human), 41..257 170/217 (78%) 258 aa.

Q98ST6 SUGARCRISP - Gallus gallus22..253 140/238 (58%)8e-90 (Chicken), 258 aa. 20..257 179/238 (74%) Q99MM7 SUGARCRISP - Mus musculus3..253 144/256 (56%)' 1e-89 (Mouse), 258 aa. 2..257 186/256 (72%) Q98ST5 COCOACRISP - Gallus gallus14..243 111/230 (48%)6e-71 (Chicken), 523 aa. 14..242 158/230 (68%) PFam analysis predicts that the NOV24a protein contains the domains shown in the Table 24E.
Table 24E. Domain Analysis of NOV24a Identities/
Pfam Domain NOV24a Match Region Similarities Expect Value for the Matched Region SCP: domain 1 of 1 67..215 54/173 (31%) 2.9e-21 96/173 (SS%) EXAMPLE 25.
The NOV25 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 25A.
Table 25A. NOV25 Sequence Analysis ~~ SEQ ID NO: 121 ~ 2345 by NOV25a, AGGAGCCGCGATGTTCCCCCTTCGGGCCCTGTGGTTGGTCTGGGCGCTTCTAGGAGTG

DNA

SequeriCe ACTGCGCTTACAAAGAGTTGCGTGAGGTGCCGGAAGGACTGCCTGCCAACGTGACGAC

GCTTAGTCTGTCCGCGAACAAGATCACTGTGCTGCGGCGCGGGGCCTTCGCCGACGTC

ACACAGGTCACGTCGCTGTGGCTGGCGCACAATGAGGTGCGCACCGTGGAGCCAGGCG

CACTGGCCGTGCTGAGTCAGCTCAAGAACCTCGATCTGAGCCACAACTTCATATCCAG

CTTTCCGTGGAGCGACCTGCGCAACCTGAGCGCGCTGCAGCTGCTCAAAATGAACCAC

AACCGCCTGGGCTCTCTGCCCCGGGACGCACTCGGTGCGCTACCCGACCTGCGTTCCC

TGCGCATCAACAACAACCGGCTGCGTACGCTGGCGCCTGGCACCTTCGACGCGCTTAG

CGCGCTGTCACACTTGCAACTCTATCACAATCCCTTCCACTGCGGCTGCGGCCTTGTG

TGGCTGCAGGCCTGGGCCGCGAGCACCCGGGTGTCCTTACCCGAGCCCGACTCCATTG

CTTGTGCCTCGCCTCCCGCGCTGCAGGGGGTGCCGGTGTACCGCCTGCCCGCCCTGCC

CTGTGCACCGCCCAGCGTGCATCTGAGTGCCGAGCCACCGCTTGAAGCACCCGGCACC

CCACTGCGCGCAGGACTGGCGTTCGTGTTACACTGCATCGCCGACGGCCACCCTACGC

CTCGCCTGCAATGGCAACTTCAGATCCCCGGTGGCACCGTAGTCTTAGAGCCACCGGT

TCTGAGCGGGGAGGACGACGGGGTTGGGGCGGAGGAAGGAGAGGGAGAAGGAGATGGG

GATTTGCTGACGCAGACCCAAGCCCAAACGCCGACTCCAGCACCCGCTTGGCCGGCGC

CCCCAGCCACACCGCGCTTCCTGGCCCTCGCAAATGGCTCCCTGTTGGTGCCCCTCCT

GAGTGCCAAGGAGGCGGGCGTCTACACTTGCCGTGCACACAATGAGCTGGGCGCCAAC

TCTACGTCAATACGCGTGGCGGTGGCAGCAACCGGGCCCCCAAAACACGCGCCTGGCG

CCGGGGGAGAACCCGACGGACAGGCCCCGACCTCTGAGCGCAAGTCCACAGCCAAGGG

CCGGGGCAACAGCGTCCTGCCTTCCAAACCCGAGGGCAAAATCAAAGGCCAAGGCCTG

GCCAAGGTCAGCATTCTCGGGGAGACCGAGACGGAGCCGGAGGAGGACACAAGTGAGG

GAGAGGAGGCCGAAGACCAGATCCTCGCGGACCCGGCGGAGGAGCAGCGCTGTGGCAA

CGGGGACCCCTCTCGGTACGTTTCTAACCACGCGTTCAACCAGAGCGCAGAGCTCAAG

CCGCACGTCTTCGAGCTGGGCGTCATCGCGCTGGATGTGGCGGAGCGCGAGGCGCGGG

TGCAGCTGACTCCGCTGGCTGCGCGCTGGGGCCCTGGGCCCGGCGGGGCTGGCGGAGC

CCCGCGACCCGGGCGGCGACCCCTGCGCCTACTCTATCTGTGTCCAGCGGGGGGCGGC

GCGGCAGTGCAGTGGTCCCGCGTAGAGGAAGGCGTCAACGCCTACTGGTTCCGCGGCC

TGCGGCCGGGTACCAACTACTCCGTGTGCCTGGCGCTGGCGGGCGAAGCCTGCCACGT

GCAAGTGGTGTTTTCCACCAAGAAGGAGCTCCCATCGCTGCTGGTCATAGTGGCAGTG

AGCGTATTCCTCCTGGTGCTGGCCACAGTGCCCCTTCTGGGCGCCGCCTGCTGCCATC

TGCTGGCTAAACACCCGGGCAAGCCCTACCGTCTGATCCTGCGGCCTCAGGCCCCTGA

CCCTATGGAGAAGCGCATCGCCGCAGACTTCGACCCGCGTGCTTCGTACCTCGAGTCC

GAGAAAAGCTACCCGGCAGGCGGCGAGGCGGGCGGCGAGGAGCCAGAGGACGTGCAGG

GGGAGGGCCTTGATGAAGACGCGGAGCAGGGAGACCCAAGTGGGGACCTGCAGAGAGA

GGAGAGCCTGGCGGCCTGCTCACTGGTGGAGTCCCAGTCCAAGGCCAACCAAGAGGAG

TTCGAGGCGGGCTCTGAGTACAGCGATCGGCTGCCCCTGGGCGCCGAGGCGGTCAACA

TCGCCCAGGAGATTAATGGCAACTACAGGCAGACGGCAGGCTGAACCTCCGCCCGTCC

GGCCCGCCCATTCCCGACCTCCACCTAGGGTGCCTGGGAGCAGCAGTCTAGGGCTGGC

AGGACTTATGTCCCCCGTCCCCAAC

ORF Start: ATG at ORF Stop:
11 TGA at SEQ ID NO: 122 2345 as MW at 78989.2 kD

NOV2Sa, MFPLRALWLVWALLGVAGSCPEPCACVDKYAHQFADCAYKELREVPEGLPANVTTLSL

CGS9S88-O1 S~KITVLRRGAFADVTQVTSLWLAHNEVRTVEPGALAVLSQLKNLDLSHNFISSFPW

PrOteln Sequence , SDLRNLSALQLLKMNHNRLGSLPRDALGALPDLRSLRINNNRLRTLAPGTFDALSALS

HLQLYHNPFHCGCGLVWLQAWAASTRVSLPEPDSIACASPPALQGVPVYRLPALPCAP

PSVHLSAEPPLEAPGTPLRAGLAFVLHCIADGHPTPRLQWQLQIPGGTVVLEPPVLSG

EDDGVGAEEGEGEGDGDLLTQTQAQTPTPAPAWPAPPATPRFLALANGSLLVPLLSAK

EAGVYTCRAHNELGANSTSIRVAVAATGPPKHAPGAGGEPDGQAPTSERKSTAKGRGN

SVLPSKPEGKIKGQGLAKVSILGETETEPEEDTSEGEEAEDQILADPAEEQRCGNGDP

SRYVSNHAFNQSAELKPHVFELGVIALDVAEREARVQLTPLAARWGPGPGGAGGAPRP

GRRPLRLLYLCPAGGGAAVQWSRVEEGVNAYWFRGLRPGTNYSVCLALAGEACHVQW

FSTKKELPSLLVIVAVSVFLLVLATVPLLGAACCHLLAKHPGKPYRLILRPQAPDPME

KRIAADFDPRASYLESEKSYPAGGEAGGEEPEDVQGEGLDEDAEQGDPSGDLQREESL

AACSLVESQSKANQEEFEAGSEYSDRLPLGAEAVNIAQEINGNYRQTAG

Further analysis of the NOV2Sa protein yielded the following properties shown in Table 2SB.

Table 25B.
Protein Sequence Properties NOV25a PSort 0.4600 probability located in plasma membrane; 0.1000 probability located in analysis:endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside SignalP Likely cleavage site between residues 19 and 20 analysis:

A search of the NOV25a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 25C.
Table 25C. Geneseq Results for NOV25a NOV25a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent for Identifier#, Date] Match the Matched Value Residues Region AAE09450 Human sbg34976IGBa protein1..745 745/745 (100%)0.0 #1 -Homo Sapiens, 745 aa. 1..745 745/745 (100%) [W0200160850-A1, 23-AUG-2001]

AAU12205 Human PR04329 polypeptide1..745 745/745 (100%)0.0 sequence - Homo Sapiens, 1..745 745/745 (100%) 745 aa.

[W0200140466-A2, 07-JUN-2001 ]

AAB40448 Human ORFX ORF212 polypeptide265..472 208/208 (100%)e-120 sequence SEQ ID N0:424 2..209 208/208 (100%) - Homo Sapiens, 209 aa. [W0200058473-A2, 05-OCT-2000]

AAM93734 Human polypeptide, SEQ 1..417 217/426 (50%)e-107 ID NO:

3699 - Homo Sapiens, 428 1..385 260/426 (60%) aa.

[EP1130094-A2, 05-SEP-2001]

AAU12317 Human PR0215 polypeptide 1..417 217/426 (50%)e-107 sequence - Homo Sapiens, 1..385 260/426 (60%) 428 aa.

[W0200140466-A2, 07-JUN-2001]

In a BLAST search of public sequence databases, the NOV25a protein was found to have homology to the proteins shown in the BLASTP data in Table 25D.
Table 25D.
Public BLASTP
Results for NOV25a NOV25a Identities/

Protein Residues/Similarities Expect for Accession Protein/Organism/LengthMatch the Matched Value Number ResiduesPortion Q9P263 KIAA1465 PROTEIN - Homo104..745642/642 (100%)0.0 1..642 642/642 (100%) (fragment).

014498 ISLR PRECURSOR - Homo 1..417 217/426 (50%) e-106 Sapiens (Human), 428 1..385 260/426 (60%) aa.

BAA85972 ISLR PRECURSOR - Mus 4..417 209/421 (49%) e-102 musculus (Mouse), 428 1..385 258/421 (60%) aa.

088279 MEGF4 - Rattus norvegicus20..246 77/232 (33%) 1e-25 (Rat), 1531 aa. 734..933 113/232 (48%) Q9WVB5 SLIT1 - Mus musculus 20..246 77/232 (33%) 1e-25 (Mouse), 1531 aa. 734..933 113/232 (48%) PFam analysis predicts that the NOV25a protein contains the domains shown in the Table 25E.
Table 25E. Domain Analysis of NOV25a Identities/

Pfam Domain NOV25a Match RegionSimilarities Expect Value for the Matched Region LRRNT: domain 19..50 12/33 (36%) 0.27 1 of 1 20/33 (61%) LRR: domain 52..75 7/25 (28%) 1.4 1 of 5 18/25 (72%) LRR: domain 76..99 5/25 (20%) 31 2 of 5 18/25 (72%) LRR: domain 100..123 11/25 (44%) 0.0026 3 of 5 20/25 (80%) LRR: domain 124..147 10/25 (40%) 0.099 4 of 5 18/25 (72%) LRR: domain 148..171 9/25 (36%) 0.14 of 5 19/25 (76%) LRRCT: domain 181..231 19/54 (35%) 1.5e-14 1 of 1 41/54 (76%) ig: domain 1 253..357 13/108 (12%) 0.01 of 1 70/108 (65%) ExAMPLE 26.
The NOV26 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 26A.
Table 26A.
NOV26 Sequence Analysis SEQ ID NO: 123 4426 by NOV26a, ATGTACTGTTTTTTGCGATCTGCCGTTTCGTTCTTCTGCCTCAGCCTCCCCAGGTGCT

SeClilellCe GATTCCTTCTGTTCTACAAGAAGGCTCTTTGGATAAAGCTTGTGCCCAGCTTTTTAAT
CTCACTGAATCTGTTGTTTTGACGGTCTCCCTCAACTATGGTGAGGTCCAGACCAAAA
TATTTGAAGAAAATGTTACTGGAGAAAATTTCTTCAAATGCATCAGCTTTGAGGTTCC
TCAGGCCAGATCTGACCCACTGGCATTTATTACATTTTCTGCTAAAGGAGCCACTCTC
AACCTGGAAGAGAGGAGATCTGTGGCAATCAGATCCAGAGAGAATGTGGTCTTTGTAC
AGACTGATAAACCCACCTACAAGCCTGGACAGTATAATAAAAAGCCGATCAGTCACAT
AATGCCAGTGATAGCAGTCACTGAACAGGATCCAGAAGGCAATCGAATACAACAGTGG
GTGAATGAGGAGTCTGTGGGAGGGATTCTACAACTCTCCTTCCAGTTAATCTCAGAGC
CCATCCTCGGATGGTATGAAATCACCGTGGAGATGCTCAATGAGAAGAAAACATATCA
CTCCTTCTCTGTGGAAGAATATGTGTTACCCAAATTTCAAATGACTGTGGATGCACCA
GAAAATATCTTAGTTGTGGACTCTGAATTCAAAGTGAATGTCTGTGCCTTGTATACCT
ATGGTGAACCTGTGGACGGGAAGGTCCAACTTAGTGTGTGCAGAGAATCTACGGCTTA
TCATTCATGTGCTCATCTTATCAGTTCACTCTGTAAAAATTTTACCTTGGGGAAAGAT
GGCTGTGTCTCCAAGTTTATTAACACAGATGCTTTTGAGTTAAATCGGGAAGGATACT
GGAGTTTCCTCAAAGTGCATGCTCTTGTTACAGAGCTTACAGGCTCCAAGTACGTATA
CATAGACTCATCAGTGGTGAAGATTAGTTTTGAGAATATGGATATGTCCTACAAACAG
GGACTCCCTTATTTTGGCCAGATTAAATTGCTTAATCCAGACAACTCTCCAATCCCAA
ATGAAGTTGTTCAGTTGCATCTGAAGGACAAAATCGTGGGAAACTACACCACAGATGT
AAATGGCATCGCTCAGTTTTTCTTGGACACATATACGTTTACATACCCAAATATCACT
TTGAAAGCAGCCTACAAGGCCAATGAAAATTGCCAGGCTCATGGCTGGGTGTTGCCTC
AATACCCTCAGCCCGAGTACTTTGCATATCGATTTTACTCCAAGATGAATAGCTTCCT
AAAGATTGTCCAAGAGATGGAAGAACTGAGATGCAACCAGCAGAAGAGGGTGCTAGTG
CACTGCATTCTCAATATGGAAGACTTTGAAGACAAAACCTACACAGCAGACTTCAATT
ATTTGGTGATTTCAAAAGGTGTAATCATTCTTCATGGGCAACAGAAAATTGAGATCAA
CGAAAATGGGAGGAAGGGCATATTTTCCATTTCTATAGACATTAACCCTGAATTAGCG
CCCTCAGTACATATGCTTGTCTATAGCTTGCATCCTGGAGGAGAAATGGTCACTGATA
GCACCCAATTCCAATTGAGAAATGTTAACATAAAGTTCTCTAACGAGCAGGGCTTACC
TGGTTCCAATGCTAGTCTCTGTCTTCAAGCGGCGCCTGTCTTATTCTGTGCCCTCAGG
GCTGTGGATAGGAATGTCCTTCTACTGAAATCTGAACAACAGCTGTCAGCTGAAAGTG
TGTATAACATGGTTCCAAGTATAGAGCCGTATGGTTATTTCTACCATGGCCTCAATCT
TGATGATGGCAAGGAAGACCCTTGCATTCCTCAGAGGGATATGTTCTACAATGGTTTA
TATTACACACCTGTAAGCAACTATGGGGATGGAGATATCTATAATATTGTCAGGAACA
TGGGTCTAAAAGTCTTTACCAATCTCCATTACCGAAAACCAGAAGTATGTGTGATGGA
GAGAAGGCTGCCACTCCCTAAGCCGCTTTATCTGGAAACAGAAAATTATGGTCCAATG
CGTAGTGTTCCGTCTAGAATTGCATCTAGTGGAATCAGAGGGGAGAATGCTGACTATG
TAGAACAGGCTATAATTCAAACAGTAAGAACAAACTTCCCAGAGACATGGATGTGGGA
CCTCGTCAGTGTCGATTCCTCAGGCTCTGCCAATCTTTCGTTCCTCATTCCTGATACG
ATAACCCAATGGGAGGCAAGTGGCTTTTGTGTGAATGGTGACGTTGGATTTGGCATTT
CCTCTACAACCACTCTAGAAGTCTCCCAACCTTTCTTTATTGAGATTGCCTCACCCTT
TTTGATTTGATTGTCAATGTCTTCAGCTACCGGAAT
ACATGTGTAGAGATTTCTGTTCAAGTGGAGGAGTCTCAGAATTATGAAGCAAATATTC
ATACCTTGAAAATCAATGGCAGTGAGGTTATTCAAGCTGGAGGGAGGAAAACAAACGT
CTGGACTATTATACCTAAGAAATTGGGCAAAGTGAATATCACTGTAGTTGCTGAGTCC
ACACTGTGGTCCAAAGCTTCTTAGTAGAGCCTGAAGGTATTGAAAAGGAAAGGACCCA
GAGTTTCCTTATCTGTACAGAAGGTGCCAAAGCCTCCAAGCAGGGAGTTTTGGACTTG
CCAAACGATGTAGTAGAAGGGTCAGCCAGAGGCTTTTTCACTGTTGTGGGGGATATTC
TAGGACTTGCCTTGCAGAATCTGGTTGTTCTCCAAATGCCCTATGGAAGTGGAGAGCA
GAATGCTGCCCTACTAGCATCTGATACTTATGTTCTGGACTATCTGAAATCTACTGAG
CAACTGACAGAGGAAGTTCAATCTAAGGCTTTCTTTCTCTTATCTAATGGTTATCAAA
GGCAATTATCTTTCAAAAACTCTGATGGTTCCTATAGTGTGTTTTGGCAGCAGAGTCA
ATGGCTCAGTGCTCTTACTTTTAAGACATTGGAGAGAATGAAAAAA
TATGTATTCATTGATGAAAATGTTCAAAAACAGACCTTAATCTGGCTTTCAAGCCAAC
AGAAAACAAGCGGCTGCTTTAAGAATGATGGCCAGCTTTTCAACCACGCCTGGCAGGG
TGGAGATGAAGAGGACATTTCACTCACTGCGTATGTTGTTGGGATGTTCTTTGAAGCT
GGGGCGGCATTGGACAGTGGTGTCACTAATGGCTATAATCATGCAATTCTAGCTTATG
CTTTTGCCTTAGCTGGAAAAGAGAAGCAAGTGGAATCTTTACTCCAAACCCTGGATCA
ATCTGCCCCAAAACTAAATAATGTCATCTACTGGGAAAGAGAAAGGAAACCCAAGACA
GAAGAATTTCCATCCTTTATTCCCTGGGCACCTTCTGCTCAGACTGAGAAGAGTTGCT
ACGTGCTGTTGGCTGTCATTTCCCGGAAAATTCCTGACCTCACCTATGCTAGTAAGAT

TGTGCAGTGGCTTGCCCAACGGATGAATTCCCATGGAGGCTTTTCTTCCAACCAGGAT

CAAAACACTGTCACCTTTAGCAGTGAAGGATCCAGTGAGATTTTCCAGGTTAACGGTC

ATAACCGCCTACTGGTCCAACGTTCAGAAGTAACACAGGCACCTGGAGAATACACAGT

AGATGTGGAAGGACACGGTTGTACATTTATCCAGGCCACCCTTAAGTACAATGTTCTC

CTACCTAAGAAGGCATCTGGATTTTCTCTTTCCTTGGAAATAGTAAAGAACTACTCTT

CGACTGCTTTTGACCTCACAGTGACCCTCAAATACACTGGAATTCGCAATAAATCCAG

TATGGTGGTTATAGATGTAAAAATGCTATCAGGATTTACTCCAACCATGTCATCCATT

GAAGAGCTTGAAAACAAGGGCCAAGTGATGAAGACTGAAGTCAAGAATGACCATGTTC

TTTTCTACTTGGAAAATGTAGGTTTTGGTCGAGCAGACAGTTTCCCTTTTTCTGTTGA

GCAGAGCAACCTTGTGTTCAACATTCAGCCAGCCCCAGCCATGGTCTACGATTATTAT

GAAAAAGAAGAATATGCCCTAGCTTTTTACAACATCGACAGTAGTTCAGTTTCCGAGT

GAGACAAAGCAATTACTAGAAGAGTTGGAGAAGCATTTCTTGTAACAAACTGATTCTT

CTGTATCAAACCTGGAAAAAAATCATGAACCATCTGACATCGTGAACAGTCTGCAGTG

GGCTATGGTTTCTTGTCAAGTCTTATTTCCTTATCATCCCATTAAATGTTGTCATTTT

GCP~AAAAAAAAA

ORF Start: ATG ORF Stop:
at 1 TGA
at 4234 SEQ ID NO: 124 1411 MW at 158867.OkD
as NOV26a, MYCFLRSAVSFFCLSLPRCWGYRCEPLCLAILLLQYVLLIPSVLQEGSLDKACAQLFN

PTOteiri S2C1i1CriCe NLEERRSVAIRSRENWFVQTDKPTYKPGQYNKKPISHIMPVIAVTEQDPEGNRIQQW

VNEESVGGILQLSFQLISEPILGWYEITVEMLNEKKTYHSFSVEEYVLPKFQMTVDAP

ENILVVDSEFKVNVCALYTYGEPVDGKVQLSVCRESTAYHSCAHLISSLCKNFTLGKD

GCVSKFINTDAFELNREGYWSFLKVHALVTELTGSKYWIDSSWKISFENMDMSYKQ

GLPYFGQIKLLNPDNSPIPNEWQLHLKDKIVGNYTTDVNGIAQFFLDTYTFTYPNIT

LKAAYKANENCQAHGWVLPQYPQPEYFAYRFYSKMNSFLKIVQEMEELRCNQQKRVLV

HCILNMEDFEDKTYTADFNYLVISKGVIILHGQQKIEINENGRKGIFSISIDINPELA

PSVHMLVYSLHPGGEMVTDSTQFQLRNVNIKFSNEQGLPGSNASLCLQAAPVLFCALR

AVDRNVLLLKSEQQLSAESWNMVPSIEPYGYFYHGLNLDDGKEDPCIPQRDMFYNGL

YYTPVSNYGDGDIYNIVRNMGLKVFTNLHYRKPEVCVMERRLPLPKPLYLETENYGPM

RSVPSRIASSGIRGENADYVEQAIIQTVRTNFPETWMWDLVSVDSSGSANLSFLIPDT

ITQWEASGFCVNGDVGFGISSTTTLEVSQPFFIEIASPFSWQNEQFDLIVNVFSYRN

TCVEISVQVEESQNYEANIHTLKINGSEVIQAGGRKTNVWTIIPKKLGKVNITWAES

KQSSACPNEGMEQQKLNWKDTWQSFLVEPEGIEKERTQSFLICTEGAKASKQGVLDL

PNDWEGSARGFFTWGDILGLALQNLVVLQMPYGSGEQNAALLASDTYVLDYLKSTE

QLTEEVQSKAFFLLSNGYQRQLSFKNSDGSYSVFWQQSQKGSIWLSALTFKTLERMKK

YVFIDENVQKQTLIWLSSQQKTSGCFKNDGQLFNHAWQGGDEEDISLTAYWGMFFEA

GAALDSGVTNGYNHAILAYAFALAGKEKQVESLLQTLDQSAPKLNNVIYWERERKPKT

EEFPSFIPWAPSAQTEKSCYVLLAVISRKIPDLTYASKIVQWLAQRMNSHGGFSSNQD

QNTVTFSSEGSSEIFQVNGHNRLLVQRSEVTQAPGEYTVDVEGHGCTFIQATLKYNVL

LPKKASGFSLSLEIVKNYSSTAFDLTVTLKYTGIRNKSSMWIDVKMLSGFTPTMSSI

EELENKGQVMKTEVKNDHVLFYLENVGFGRADSFPFSVEQSNLVFNIQPAPAMVYDYY

EKEEYALAFYNIDSSSVSE

SEQ ID NO: 12S 4501 by NOV26b, TCCATTTCTATAGACATTAACCCTGAATTAGCGCCCTCAGTAGATATGCTTGTCTATA

DNA

CTTCGAAAATCAGGTCAACTTAAATTTTTCTAAAGAAAAAAGTTTACCAGGATCCAAT
SeCIUOriCe ATTGATCTTCAAGTCTCGGCTGCTTCAAACTCTCTTTGTGCTCTTTGGGCTGTAGACC

AGAGTGTATTGCTACTAAGGAATTATGGTCAGCTGTCAGCACAAACTGTGTATAGTCA

GCTATATTCCAGGGAACTACATGGCTATTACTTCAGAGGACTTAACTTAGAAGATGGC

CTTAAAGTGCCGTGTCTTGAAGATGAACATATCCTTTACAATGGAATTTATTACACAC

CTGCATGGGCTGACTTTGGAAAAGATGGCTATGACCTTGTGAAGGATCCTCAAAACAA

TCGGATTTTTCAAAGGCAAAATGTGACTTCTTTCCGAAATATTACCCAACTCTCGTTC

CAACTGATTTCAGAACCAATGTTTGGAGATTACTGGATTGTTGTGAAAAGAAACTCAA

GGGAGACAGTGACACACCAATTTGCTGTTAAAAGATATGTGCTGCCCAAGTTTGAAGT

TACAGTCAATGCACCACAAACAGTAACTATTTCAGATGATGAATTCCAAGTGGATGTA

TGTGCTAAGTACAACTTTGGCCAACCTGTGCAAGGGGAAACCCAAATCCGGGTGTGCA

GAGAGTATTTTTCTTCAAGCAATTGTGAGAAAAATGAAAATGAAATATGTGAGCAATT

TATTGCACAGTTGGAAAATGGTTGTGTTTCTCAAATTGTAAATACAAAAGTCTTCCAA

CTCTACCGTTCGGGATTGTTCATGACATTTCATGTCGCTGTAATTGTTACAGAATCTG
GGACAGTTATGCAGATCAGCGAGAAGACCTCAGTTTTTATCACTCAATTGCTTGGAAC
TGTAAACTTTGAGAACATGGATACATTCTATAGAAGAGGGATTTCTTATTTTGGAACT
CTTAAATTTTCGGATCCCAATAATGTACCTATGGTGAACAAGTTGTTGCAACTGGAGC
TCAATGATGAATTTATAGGAAATTACACTACGGATGAGAATGGCGAAGCTCAATTTTC
CATTGACACTTCAGACATATTTGATCCAGAGTTCAACCTAAAAGCCACATATGTTCGA
CCTGAGAGCTGCTATCTTCCCAGCTGGTTGACGCCTCAGTACTTGGATGCTCACTTCT
TAGTCTCACGCTTTTACTCCCGAACCAACAGCTTCCTGAAGATTGTTCCAGAACCAAA
GCAGCTTGAATGTAATCAACAGAAGGTTGTTACTGTGCATTACTCCCTAAACAGTGAA
GCATATGAGGATGATTCCAATGTAAAGTTCTTCTATTTGATGATGGTAAAAGGAGCTA
TCTTACTCAGTGGACAAAAGGAAATCAGAAACAAAGCCTGGAATGGAAACTTCTCGTT
CCCAATCAGCATCAGTGCTGATCTGGCTCCTGCAGCCGTCCTGTTTGTCTATACCCTT
CACCCCAGTGGGGAAATTGTGGCTGACAGTGTCAGATTCCAGGTTGACAAGTGCTTTA
AACACAAGGTTAACATAAAGTTCTCTAACGAGCAGGGCTTACCTGGTTCCAATGCTAG
TCTCTGTCTTCAAGCGGCGCCTGTCTTATTCTGTGCCCTCAGGGCTGTGGATAGGAAT
GTCCTTCTACTGAAATCTGAACAACAGCTGTCAGCTGAAAGTGTGTATAACATGGTTC
CAAGTATAGAGCCGTATGGTTATTTCTACCATGGCCTCAATCTTGATGATGGCAAGGA
CCTCAGAGGGATATGTTCTACAATGGTTTATATTACACACCTGTA
ATCTATAATATTGTCAGGAACATGGGTCTAAAAGTCT
TTACCAATCTCCATTACCGAAAACCAGAAAAAATTATGGTCCAATGCGTAGTGTTCCG
TCTAGAATTGCATGTAGCTAGTGGAATCAGAGGGGAGAATGCTGACTATGTAGAACAG
GCTATAATTCAAACAGTAAGAACAAACTTCCCAGAGACATGGATGTGGGACCTCGTCA
GTGTCGATTCCTCAGGCTCTGCCAATCTTTCGTTCCTCATTCCTGATACGATAACCCA
ATGGGAGGCAAGTGGCTTTTGTGTGAATGGTGACGTTGGATTTGGCATTTCCTCTACA
CAACCTTTCTTTATTGAGATTGCCTCACCCTTTTCGGTTG
TTCAAAATGAACAATTTGATTTGATTGTCAATGTCTTCAGCTACCGGAATACATGTGT
AGAGATTTCTGTTCAAGTGGAGGAGTCTCAGAATTATGAAGCAAATATTCATACCTTG
AAAATCAATGGCAGTGAGGTTATTCAAGCTGGAGGGAGGAAAACAAACGTCTGGACTA
TTATACCTAAGAAATTGGGTAAAGTGAATATCACTGTAGTTGCTGAGTCCAAACAAAG
CAGTGCTTGCCCAAATGAAGGAATGGAGCAGCAAAAGCTAAACTGGAAAGACACTGTG
GTCCAAAGCTTCTTAGTAGAGCCTGAAGGTATTGAAAAGGAAAGGACCCAGAGTTTCC
TTATCTGTACAGAAGGTGCCAAAGCCTCCAAGCAGGGAGTTTTGGACTTGCCAAACGA
TGTAGTAGAAGGGTCAGCCAGAGGCTTTTTCACTGTTGTGGGGGATATTCTAGGACTT
GCCTTGCAGAATCTGGTTGTTCTCCAAATGCCCTATGGAAGTGGAGAGCAGAATGCTG
CCCTACTAGCATCTGATACTTATGTTCTGGACTATCTGAAATCTACTGAGCAACTGAC
AAGGCTTTCTTTCTCTTATCTAATGGTTATCAAAGGCAATTA
TCTTTCAAAAACTCTGATGGTTCCTATAGTGTGTTTTGGCAGCAGAGTCAGAAAGGAA
GCATATGGCTCAGTGCTCTTACTTTTAAGACATTGGAGAGAATGAAAAAATATGTATT
CATTGATGAAAATGTTCAAAAACAGACCTTAATCTGGCTTTCAAGCCAACAGAAAACA
AAGAATGATGGCCAGCTTTTCAACCACGCCTGGGAGGGTGGAGATG
CTACGAAACGCACTCTTTTGCCTTGAAGCGGCATTGGACAGT
GGTGTCACTAATGGCTATAATCATGCAATTCTAGCTTATGCTTTTGCCTTAGCTGGAA
AAGAGAAGCAAGTGGAATCTTTACTCCAAACCCTGGATCAATCTGCCCCAAAACTAAA
TAATGTCATCTACTGGGAAAGAGAAAGGAAACCCAAGACAGAAGAATTTCCATCCTTT
ATTCCCTGGGCACCTTCTGCTCAGACTGAGAAGAGTTGCTACGTGCTGTTGGCTGTCA
TTTCCCGGAAAATTCCTGACCTCACCTATGCTAGTAAGATTGTGCAGTGGCTTGCCCA
ACGGATGAATTCCCATGGAGGCTTTTCTTCCAACCAGACACCTGATGATACTCTGTTC
AAATTATATACGGGCCAAAAAGAAAGCTTTCGCTCTAGTTCTGTGGGCTATACACTGG
GAAAAGCAAATGAAAAGAAGGAAAACAGGAGAAATGGGGGTGAAGGATCCAGTGAGAT
TTTCCAGGTTAACGGTCATAACCGCCTACTGGTCCAACGTTCAGAAGTAACACAGGCA
CCTGGAGAATACACAGTAGATGTGGAAGGACACGGTTGTACATTTATCCAGGCCACCC
TTAAGTACAATGTTCTCCTACCTAAGAAGGCATCTGGATTTTCTCTTTCCTTGGAAAT
AGTAAAGAACTACTCTTCGACTGCTTTTGACCTCACAGTGACCCTCAAATACACTGGA
ATTCGCAATAAATCCAGTATGGTGGTTATAGATGTAAAAATGCTATCAGGATTTACTC
CAACCATGTCATCCATTGAAGAGCTTGAAAACAAGGGCCAAGTGATGAAGACTGAAGT
CAAGAATGACCATGTTCTTTTCTACTTGGAAAATGTAGGTTTTGGTCGAGCAGACAGT
TTCCCTTTTTCTGTTGAGCAGAGCAACCTTGTGTTCAACATTCAGCCAGCCCCAGCCA
TGGTCTACGATTATTATGAAAAAGAAGAATATGCCCTAGCTTTTTACAACATCGACAG
TAGTTCAGTTTCCGAGTGAGACAAAGCAATTACTAGAAGAGTTGGAGAAGCATTTCTT
GTAACAAACTGATTCTTCTGTATCAAACCTGGAAAAAAATCATGAACCATCTGACATC
17~

GTGAACAGTCTGCAGTGGGCTATGGTTTCTTGTCAAGTCTTATTTCCTTATCATCCCA

TTAAATGTTGTCATTTTGC

ORF' Start: TCC ORF Stop:
at 1 TGA at SEQ ID NO: 126 1436 as MW at 161836.4kD

NOV26b, SISIDINPELAPSVDMLWSLHPGGEMVTDSTQFRIEKCFENQVNLNFSKEKSLPGSN

P1'Oteln SeqLlenCe L~PCLEDEHILYNGIYYTPAWADFGKDGYDLVKDPQNNRIFQRQNVTSFRNITQLSF

QLISEPMFGDYWIWKRNSRETVTHQFAVKRYVLPKFEVTVNAPQTVTISDDEFQVDV

CAKYNFGQPVQGETQIRVCREYFSSSNCEKNENEICEQFIAQLENGCVSQIVNTKVFQ

LYRSGLFMTFHVAVIVTESGTVMQISEKTSVFITQLLGTVNFENMDTFYRRGISYFGT

LKFSDPNNVPMVNKLLQLELNDEFIGNYTTDENGEAQFSIDTSDIFDPEFNLKATYVR

PESCYLPSWLTPQYLDAHFLVSRFYSRTNSFLKIVPEPKQLECNQQKVVTVHYSLNSE

AYEDDSNVKFFYLMMVKGAILLSGQKEIRNKAWNGNFSFPISISADLAPAAVLFVYTL

HPSGEIVADSVRFQVDKCFKHKVNIKFSNEQGLPGSNASLCLQAAPVLFCAI~RAVDRN

VLLLKSEQQLSAESVYNMVPSIEPYGYFYHGLNLDDGKEDPCIPQRDMFYNGLYYTPV

SNYGDGDIYNIVRNMGLKVFTNLHYRKPEKIMVQCWFRLELHVASGIRGENADYVEQ

AIIQTVRTNFPETWMWDLVSVDSSGSANLSFLIPDTITQWEASGFCVNGDVGFGISST

TTLEVSQPFFIEIASPFSWQNEQFDLIVNVFSYRNTCVEISVQVEESQNYEANIHTL

KINGSEVIQAGGRKTNVWTIIPKKLGKVNITWAESKQSSACPNEGMEQQKLNWKDTV

VQSFLVEPEGIEKERTQSFLICTEGAKASKQGVLDLPNDWEGSARGFFTWGDILGL

ALQNLWLQMPYGSGEQNAALLASDTYVLDYLKSTEQLTEEVQSKAFFLLSNGYQRQL

SFKNSDGSYSVFWQQSQKGSIWLSALTFKTLERMKKYVFIDENVQKQTLIWLSSQQKT

SGCFKNDGQLFNHAWEGGDEEDISLTAYWGMFFEAGLNFTFPALRNALFCLEAALDS

GVTNGYNHAILAYAFALAGKEKQVESLLQTLDQSAPKLNNVIYWERERKPKTEEFPSF

IPWAPSAQTEKSCYVLLAVISRKIPDLTYASKIVQWLAQRMNSHGGFSSNQTPDDTLF

KLYTGQKESFRSSSVGYTLGKANEKKENRRNGGEGSSEIFQVNGHNRLLVQRSEVTQA

PGEYTVDVEGHGCTFIQATLKYNVLLPKKASGFSLSLEIVKNYSSTAFDLTVTLKYTG

IRNKSSMWIDVKMLSGFTPTMSSIEELENKGQVMKTEVKNDHVLFYLENVGFGRADS

FPFSVEQSNLVFNIQPAPAMVYDYYEKEEYALAFYNIDSSSVSE

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 26B.
Table 26B.
Comparison of NOV26a against NOV26b and NOV26c.

Protein SequenceNOV26a Residues/Identities/

Match ResiduesSimilarities for the Matched Region NOV26b 164..1411 997/1311 (76%) 150..1436 1072/1311 (81%) Further analysis of the NOV26a protein yielded the following properties shown in Table 26C.
Table 26C. Protein Sequence Properties NOV26a PSort 0.8200 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1380 probability located in microbody (peroxisome);
0.1000 probability located in endoplasmic reticulum (membrane) SignalP ~ Likely cleavage site between residues 46 and 47 analysis:

A search of the NOV26a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 26D.
Table 26D. Geneseq Results for NOV26a NOV26a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent for Identifier#, Date] Match the Matched Value Residues Region AAB50673Human alpha-2 macroglobulin35..1407 552/1458 0.0 (37%) protein SEQ ID N0:59 - 30..1468 846/1458 Homo (57%) Sapiens, 1474 aa. [W0200073328-A2, 07-DEC-2000]

AAY97157Human alpha-2-macroglobulin35..1407 551/1458 0.0 - (37%) Homo Sapiens, 1474 aa. 30..1468 846/1458 (57%) [W0200046246-A1, 10-AUG-2000]

AAR11334Recombinant human alpha-235..1407 549/1458 0.0 (37%) macroglobulin - Homo Sapiens,30..1468 844/1458 1474 (57%) aa. [W09103557-A, 21-MAR-1991]

AAR11749Human alpha-2 macroglobulin35..1407 546/1460 0.0 bait (37%) region mutant - Homo sapiens,30..1478 842/1460 1484 (57%) aa. [W09103557-A, 21-MAR-1991]

AAB43949Human cancer associated 187..1407497/1295 0.0 protein (38%) sequence SEQ ID N0:1394 2..1279 753/1295 - Homo (57%) Sapiens, 1285 aa. [W0200055350-Al, 21-SEP-2000]

In a BLAST search of public sequence databases, the NOV26a protein was found to have homology to the proteins shown in the BLASTP data in Table 26E.
Table 26E. Public BLASTP Results for NOV26a Protein NOV26a Identities/
AccessionProtein/Organism/Length Residues/Similarities Expect Number Match for Value Residuesthe Matched Portion P20740 Ovostatin precursor 1..1402 640/1482 (43%)0.0 (Ovomacroglobulin) - 1..1461 931/1482 (62%) Gallus gallus (Chicken), 1473 aa.

P01023 Alpha-2-macroglobulin 35..1407552/1458 (37%)0.0 precursor (Alpha-2-M) - Homo Sapiens30..1468846/1458 (57%) (Human), 1474 aa.

CAA01532 ALPHA 2-MACROGLOBULIN 35..1407550/1458 (37%)0.0 30..1468845/1458 (57%) 1474 aa.

P06238 Alpha-2-macroglobulin precursor 552/1477 (37%) 0.0 26..1408 (Alpha-2-M) - Rattus norvegicus 852/1477 (57%) 13..1467 (Rat), 1472 aa.

CAA01533 ALPHA 2-MACROGLOBULIN 35..1407 547/1460 (37%) 0.0 690-740 - Homo sapiens (Human), 844/1460 (57%) 30..1478 1484 aa.

PFam analysis predicts that the NOV26a protein contains the domains shown in the Table 26F.
Table 26F. Domain Analysis of NOV26a Identities/

Pfam Domain NOV26a Match Similarities Expect Region for the Matched Value Region A2M_N: domain 1 of 1 35..611 178/655 (27%) 3.3e-96 381/655 (58%) A2M: domain 1 of 3 717..1096 137/414 (33%) 2.2e-95 268/414 (65%) prenyltrans: domain 1 of 1194..12147/21 (33%) 4.4 1 15/21 (71 %) A2M: domain 2 of 3 1114..1218 45/110 (41%) 1e-19 72/110 (65%) A2M: domain 3 of 3 1226..1402 61/242 (25%) 1.1e-35 125/242 (52%) EXAMPLE 27.
The NOV27 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 27A.
Table 27A. NOV27 Sequence Analysis SEQ ID NO: 127 880 by NOV27a, ACTCACTATAGGGCTCGAGCGGCACCATGGCTTTCCTCTGGCTCCTCTCCTGCTGGGC

DNA

CTGTCCAGGATCGTGAATGGGGAGGACGCCGTCCCCGGCTCCTGGCCCTGGCAGGTGT
Sequence CCCTGCAGGACAAAACCGGCTTCCACTTCTGCGGGGGCTCCCTCATCAGCGAGGACTG

GGTGGTCACCGCTGCCCACTGCGGGGTCAGGACCTCCGACGTGGTCGTGGCTGGGGAG

TTTGACCAGGGCTCTGACGAGGAGAACATCCAGGTCCTGAAGATCGCCAAGGTCTTCA

AGAACCCCAAGTTCAGCATTCTGACCGTGAACAATGACATCACCCTGCTGAAGCTGGC

CACACCTGCCCGCTTCTCCCAGACAGTGTCCGCCGTGTGCCTGCCCAGCGCCGACGAC

GACTTCCCCGCGGGGACACTGTGTGCCACCACAGGCTGGGGCAAGACCAAGTACAACG

CCAACAAGACCCCTGACAAGCTGCAGCAGGCAGCCCTGCCCCTCCTGTCCAATGCCGA

ATGCAAGAAGTCCTGGGGCAGGAGGATCACCGACGTGATGATCTGTGCCGGGGCCAGT

GGCGTCTCCTCCTGCATGGGTGACTCTGGAGGCCCCCTGGTCTGCCAGAAGGACGGAG

CCTGGACCCTGGTGGGCATTGTGTCCTGGGGCAGCCGCACCTACTCTACCACCACGCC

CGCTGTGTACGCCCGTGTCACCAAGCTCATACCCTGGGTGCAGAAGATCCTGGCCGCC
AACTGAGCCCGCAGCTCCTGCCACCCCTGCCTTAAGATTTCCCATTAAATGCATCTGT' TTAGAAAAAA
ORF Start: ATG at 27 ORF Stop: TGA at 816 SEQ ID NO: 128 263 as MW at 28046.9kD
NOV27a, MAFLWLLSCWALLGTTFGCGVPAIHPVFSGLSRIVNGEDAVPGSWPWQVSLQDKTGFH', CGS9417-O1 FCGGSLISEDWVVTAAHCGVRTSDVWAGEFDQGSDEENIQVLKIAKVFKNPKFSILT', PrOtelri Sequence ~DITLLKLATPARFSQTVSAVCLPSADDDFPAGTLCATTGWGKTKYNANKTPDKLQ''~

QAALPLLSNAECKKSWGRRITDVMICAGASGVSSCMGDSGGPLVCQKDGAWTLVGIVS

WGSRTYSTTTPAVYARVTKLIPWVQKILAAN

Further analysis of the NOV27a protein yielded the following properties shown in Table 27B.
Table 27B. Protein Sequence Properties NOV27a PSort 0.3700 probability located in outside; 0.1040 probability located in microbody analysis:(peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane);

0.1000 probability located in endoplasmic reticulum (lumen) SignalPLikely cleavage site between residues 19 and 20 analysis:

A search of the NOV27a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 27C.
Table 27C. Geneseq Results for NOV27a NOV27a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate) Match the Matched Value ResiduesRegion AAB98S04Human chymotrypsin serine 33..263 226/231 (97%)e-132 protease catalytic domain - Homo 1..231 228/231 (97%) Sapiens, 231 aa. [W0200129056-A1, 26-APR-2001 ]

AAY99S96Bovine chymotrypsinogen 19..263 197/245 (80%)e-116 A - Bos taurus, 245 aa. [W0200032759-A1,1..245 213/245 (86%) 08-JUN-2000]

AAB11711Mouse serine protease BSSPS1..263 150/264 (S6%)Se-87 (mBSSPS) SEQ ID N0:4 - 1..264 188/264 (70%) Mus sp, 264 aa. [W0200031243-A1, 2000]

AAB11710Human serine protease BSSPS1..263 141/264 (S3%)2e-82 (hBSSPS) SEQ ID N0:2 - 1..264 184/264 (69%) Homo Sapiens, 264 aa. [W0200031243-Al, 02-JUN-2000]

AAB54190 Human pancreatic cancer antigen 132..263 127/132 (96%) 1e-71 protein sequence SEQ ID N0:642 - 2..133 129/132 (97%) Homo sapiens, 133 aa.
[W0200055320-A1, 21-SEP-2000]
In a BLAST search of public sequence databases, the NOV27a protein was found to have homology to the proteins shown in the BLASTP data in Table 27D.
Table 27D. Public BLASTP Results for NOV27a NOV27a Identities/

Protein Residues/Similarities Expect for AccessionProtein/Organism/Length Match the Matched Value Number ResiduesPortion P17538 Chymotrypsinogen B precursor1..263 257/263 (97%)e-152 (EC

3.4.21.1) - Homo sapiens1..263 259/263 (97%) (Human), 263 aa.

P04813 Chymotrypsinogen 2 precursor1..263 228/263 (86%)e-135 (EC

3.4.21.1) - Canis familiaris1..263 241/263 (90%) (Dog), 263 aa.

Q9CR35 2200008D09RIK PROTEIN 1..263 223/263 (84%)e-135 - Mus musculus (Mouse), 263 1..263 246/263 (92%) aa.

P07338 Chymotrypsinogen B precursor1..263 222/263 (84%)e-135 (EC

3.4.21.1 ) - Rattus norvegicus1..263 244/263 (92%) (Rat), 263 aa.

Q9DC86 2200008D09RIK PROTEIN 1..263 222/263 (84%)e-134 - Mus musculus (Mouse), 263 1..263 246/263 (93%) aa.

PFam analysis in the predicts that the NOV27a protein contains the domains shown Table 27E.
Table 27E. Domain Analysis of NOV27a Identities/
Pfam Domain NOV27a Match Region Similarities Expect Value for the Matched Region trypsin: domain 1 of 1 34..256 109/261 (42%) 5.6e-102 194/261 (74%) EXAMPLE 28.
The NOV28 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 28A.
Table 28A. NOV28 Sequence_Analysis SEQ ID NO: 129 1749 by NOV28a, GCGGTCCCCAGCCTGGGTAAAGATGGCCCCATGGCCCCCGAAGGGCCTAGTCCCAGCT

DNA

CTCCACCTCCCCAGTCTTCTCCCCCGCCTCAGCCCCATCCGTGTCATACCTGCCGGGG
SeClileriCe ACTGGTTGACAGCTTTAACAAGGGCCTGGAGAGAACCATCCGGGACAACTTTGGAGGT

GGAAACACTGCCTGGGAGGAAGAGAATTTGTCCAAATACAAAGACAGTGAGACCCGCC

TGGTAGAGGTGCTGGAGGGTGTGTGCAGCAAGTCAGACTTCGAGTGCCACCGCCTGCT

GGAGCTGAGTGAGGAGCTGGTGGAGAGCTGGTGGTTTCACAAGCAGCAGGAGGCCCCG

GACCTCTTCCAGTGGCTGTGCTCAGATTCCCTGAAGCTCTGCTGCCCCGCAGGCACCT

TCGGGCCCTCCTGCCTTCCCTGTCCTGGGGGAACAGAGAGGCCCTGCGGTGGCTACGG

GCAGTGTGAAGGAGAAGGGACACGAGGGGGCAGCGGGCACTGTGACTGCCAAGCCGGC

TACGGGGGTGAGGCCTGTGGCCAGTGTGGCCTTGGCTACTTTGAGGCAGAACGCAACG

CCAGCCATCTGGTATGTTCGGCTTGTTTTGGCCCCTGTGCCCGATGCTCAGGACCTGA

GGAATCAAACTGTTTGCAATGCAAGAAGGGCTGGGCCCTGCATCACCTCAAGTGTGTA

GACATTGATGAGTGTGGCACAGAGGGAGCCAACTGTGGAGCTGACCAATTCTGCGTGA

ACACTGAGGGCTCCTATGAGTGCCGAGACTGTGCCAAGGCCTGCCTAGGCTGCATGGG

GGCAGGGCCAGGTCGCTGTAAGAAGTGTAGCCCTGGCTATCAGCAGGTGGGCTCCAAG

TGTCTCGATGTGGATGAGTGTGAGACAGAGGTGTGTCCCGGGAGAGAACAAGCCCAGT

GTGAAAACACCGAGGGCGGTTATCGCTGCATCTGTGCCGAGGGCTACAAGCAGATGGA

AGGCATCTGTGTGAAGGAGCAGATCCCAGAGTCAGCAGGCTTCTTCTCAGAGATGACA

GAAGACGAGTTGGTGGTGCTGCAGCAGATGTTCTTTGGCATCATCATCTGTGCACTGG

CCACGCTGGCTGCTAAGGGGGACTTGGTGTTCACCGCCATCTTCATTGGGGCTGTGGC

GGCCATGACTGGGTACTGGTTGTCAGAGCGCAGTGACCGTGTGCTGGAGGGCTTCATC

AAGGGCAGATAATCGCGGCCACCACCTGTAGGACCTCCTCCCACCCACGCTGCCCCCA

GAGCTTGGGCTGCCCTCCTGCTGGACACTCAGGACAGCTTGGTTTATTTTTGAGAGTG

GGGTAAGCACCCCTACCTGCCTTACAGAGCAGCCCAGGTACCCAGGCCCGGGCAGACA

AGGCCCCTGGGGTAAAAAGTAGCCCTGAAGGTGGATACCATGAGCTCTTCACCTGGCG

GGGACTGGCAGGCTTCACAATGTGTGAATTTCAAAAGTTTTTCCTTAATGGTGGCTGC

TAGAGCTTTGGCCCCTGCTTAGGATTAGGTGGTCCTCACAGGGGTGGGGCCATCACAG

CTCCCTCCTGCCAGCTGCATGCTGCCAGTTCCTGTTCTGTGTTCACCACATCCCCACA

CCCCATTGCCACTTATTTATTCATCTCAGGAAATAAAGAAAGGTCTTGGAAAGTTAAA

AAAAAAAAA
ORF Start: ATG at 23 ORF Stop: TAA at 1286 SEQ ID NO: 130 421 as MW at 4SS20.1kD

NOV28a, MAPWPPKGLVPAVLWGLSLFLNLPGPIWLQPSPPPQSSPPPQPHPCHTCRGLVDSFNK

PrOtelri Se ileriCe ESWWFHKQQEAPDLFQWLCSDSLKLCCPAGTFGPSCLPCPGGTERPCGGYGQCEGEGT

RGGSGHCDCQAGYGGEACGQCGLGYFEAERNASHLVCSACFGPCARCSGPEESNCLQC

KKGWALHHLKCVDIDECGTEGANCGADQFCVNTEGSYECRDCAKACLGCMGAGPGRCK

KCSPGYQQVGSKCLDVDECETEVCPGREQAQCENTEGGYRCICAEGYKQMEGICVKEQ

IPESAGFFSEMTEDELVVLQQMFFGIIICALATLAAKGDLVFTAIFIGAVAAMTGYWL

SERSDRVLEGFIKGR

SEQ ID NO: 131 1011 by NOV28b, GGATCCCAGCCCTCTCCACCTCCCCAGTCTTCTCCCCCGCCTCAGCCCCATCCGTGTC

CAACTTTGGAGGTGGAAACACTGCCTGGGAGGAAGAGAATTTGTCCAAATACAAAGAC
SeC111eriCe AGTGAGACCCGCCTGGTAGAGGTGCTGGAGGGTGTGTGCAGCAAGTCAGACTTCGAGT

GCCACCGCCTGCTGGAGCTGAGTGAGGAGCTGGTGGAGAGCTGGTGGTTTCACAAGCA

GCAGGAGGCCCCGGACCTCTTCCAGTGGCTGTGCTCAGATTCCCTGAAGCTCTGCTGC

CCCGCAGGCACCTTCGGGCCCTCCTGCCTTCCCTGTCCTGGGGGAACAGAGAGGCCCT

GCGGTGGCTACGGGCAGTGTGAAGGAGAAGGGACACGAGGGGGCAGCGGGCACTGTGA

CTGCCAAGCCGGCTACGGGGGTGAGGCCTGTGGCCAGTGTGGCCTTGGCTACTTTGAG

GCAGAACGCAACGCCAGCCATCTGGTATGTTCGGCTTGTTTTGGCCCCTGTGCCCGAT

GCTCAGGACCTGAGGAATCAAACTGTTTGCAATGCAAGAAGGGCTGGGCCCTGCATCA

CCTCAAGTGTGTAGACATTGATGAGTGTGGCACAGAGGGAGCCAACTGTGGAGCTGAC

CAATTCTGCGTGAACACTGAGGGCTCCTATGAGTGCCGAGACTGTGCCAAGGCCTGCC

TAGGCTGCATGGGGGCAGGGCCAGGTCGCTGTAAGAAGTGTAGCCCTGGCTATCAGCA

GGTGGGCTCCAAGTGTCTCGATGTGGATGAGTGTGAGACAGAGGTGTGTCCGGGAGAG

AACAAGCAGTGTGAAAACACCGAGGGCGGTTATCGCTGCATCTGTGCCGAGGGCTACA

AGCAGATGGAAGGCATCTGTGTGAAGGAGCAGATCCCAGAGTCAGCAGGCTTCTTCTC

AGAGATGACAGAAGACGAGCTCGAG

ORF Start: GGA at ORF Stop:

SEQ ID NO: 132 337 as MW at 363S2.1kD

NOV2Hb, GSQPSPPPQSSPPPQPHPCHTCRGLVDSFNKGLERTIRDNFGGGNTAWEEENLSKYKD

PrOtelri SeClllBriCe PAGTFGPSCLPCPGGTERPCGGYGQCEGEGTRGGSGHCDCQAGYGGEACGQCGLGYFE

AERNASHLVCSACFGPCARCSGPEESNCLQCKKGWALHHLKCVDIDECGTEGANCGAD

QFCVNTEGSYECRDCAKACLGCMGAGPGRCKKCSPGYQQVGSKCLDVDECETEVCPGE

NKQCENTEGGYRCICAEGYKQMEGICVKEQIPESAGFFSEMTEDELE

SEQ ID NO: 133 1011 by NOV2HC, GGATCCCAGCCCTCTCCACCTCCCAAGTCTTCTCCCCCGCCTCAGCCCCATCCGTGTC

DNA

CAACTTTGGAGGTGGAAACACTGCCTGGGAGGAAGAGAATTTGTCCAAATACAAAGAC
S0C1L1eriC2 AGTGAGACCCGCCTGGTAGAGGTGCTGGAGGGTGTGTGCAGCAAGTCAGACTTCGAGT

GCCACCGCCTGCTGGAGCTGAGTGAGGAGCTGGTGGAGAGCTGGTGGTTTCACAAGCA

GCAGGAGGCCCCGGACCTCTTCCAGTGGCTGTGCTCAGATTCCCTGAAGCTCTGCTGC

CCCGCAGGCACCTTCGGGCCCTCCTGCCTTCCCTGTCCTGGGGGAACAGAGAGGCCCT

GCGGTGGCTGCGGGCAGTGTGAAGGAGAAGGGACACGAGGGGGCAGCGGGCACTGTGA

CTGCCAAGCCGGCTACGGGGGTGAGGCCTGTGGCCAGTGTGGCCTTGGCTACTTTGAG

GCAGAACGCAACGCCAGCCATCTGGTATGTTCGGCTTGTTTTGGCCCCTGTGCCCGAT

GCTCAGGACCTGAGGAATCAAACTGTTTGCAATGCAAGAAGGGCTGGGCCCTGCATCA

CCTCAAGTGTGTAGACATTGATGAGTGTGGCACAGAGGGAGCCAACTGTGGAGCTGAC

CAATTCTGCGTGAACACTGAGGGCTCCTATGAGTGCCGAGACTGTGCCAAGGCCTGCC

TAGGCTGCATGGGGGCAGGGCCAGGTCGCTGTAAGAAGTGTAGCCCTGGCTATCAGCA

GGTGGGCTCCAAGTGTCTCGATGTGGATGAGTGTGAGACAGAGGTGTGTCCGGGAGAG

AACAAGCAGTGTGAAAACACCGAGGGCGGTTATCGCTGCATCTGTGCCGAGGGCTACA

AGCAGATGGAAGGCATCTGTGTGAAGGAGCAGATCCCAGAGTCAGCAGGCTTCTTCTC

AGAGATGACAGAAGACGAGCTCGAG

ORF Start: GGA at ORF Stop:

SEQ ID NO: 134 337 as MW at 36292.1kD

NOV28C, GSQPSPPPKSSPPPQPHPCHTCRGLVDSFNKGLERTIRDNFGGGNTAWEEENLSKYKD

191$1S724 SETRLVEVLEGVCSKSDFECHRLLELSEELVESWWFHKQQEAPDLFQWLCSDSLKLCC

PrOtelri Se ileriC2 PAGTFGPSCLPCPGGTERPCGGCGQCEGEGTRGGSGHCDCQAGYGGEACGQCGLGYFE

AERNASHLVCSACFGPCARCSGPEESNCLQCKKGWALHHLKCVDIDECGTEGANCGAD

QFCVNTEGSYECRDCAKACLGCMGAGPGRCKKCSPGYQQVGSKCLDVDECETEVCPGE

NKQCENTEGGYRCICAEGYKQMEGICVKEQIPESAGFFSEMTEDELE

SEQ ID NO: 13S 1646 by NOV2gCl, GGCGACGCGGTCCCCAGCCTGGGTAAAGATGGCCCCATGGCCCCCGAAGGGCCTAGTC

DNA

AGCCCTCTCCACCTCCCCAGTCTTCTCCCCCGCCTCAGCCCCATCCGTGTCATACCTG
SeCjLleriCe CCGGGGACTGGTTGACAGCTTTAACAAGGGCCTGGAGAGAACCATCCGGGACAACTTT

GGAGGTGGAAACACTGCCTGGGAGGAAGAGAATTTGTCCAAATACAAAGACAGTGAGA

CCCGCCTGGTAGAGGTGCTGGAGGGTGTGTGCAGCAAGTCAGACTTCGAGTGCCACCG

CCTGCTGGAGCTGAGTGAGGAGCTGGTGGAGAGCTGGTGGTTTCACAAGCAGCAGGAG

GCCCCGGACCTCTTCCAGTGGCTGTGCTCAGATTCCCTGAAGCTCTGCTGCCCCGCAG

GCACCTTCGGGCCCTCCTGCCTTCCCTGTCCTGGGGGAACAGAGAGGCCCTGCGGTGG

CTACGGGCAGTGTGAAGGAGAAGGGACACGAGGGGGCAGCGGGCACTGTGACTGCCAA

GCCGGCTACGGGGGTGAGGCCTGTGGCCAGTGTGGCCTTGGCTACTTTGAGGCAGAAC

GCAACGCCAGCCATCTGGTATGTTCGGCTTGTTTTGGCCCCTGTGCCCGATGCTCAGG

ACCTGAGGAATCAAACTGTTTGCAATGCAAGAAGGGCTGGGCCCTGCATCACCTCAAG

TGTGTAGACTGTGCCAAGGCCTGCCTAGGCTGCATGGGGGCAGGGCCAGGTCGCTGTA

AGAAGTGTAGCCCTGGCTATCAGCAGGTGGGCTCCAAGTGTCTCGTGAGTCTCCTGCT

GATGGACACAGGCACCGGCTCACCCAGCATGAATGGTGAAGAGGCTGGAATATGGGCA

GGTGGGGGAAGGAAGGGTGGAATGTTGCCTGGGCAGAGGGGAGGAGATGGACAAGATG

GAGTCAGGTGCTGGGTGGGGGGCCCTAGCAGGACTCTGACCCCTCCCTCCCCTCAAGA

TGTGGATGAGTGTGAGACAGAGGTGTGTCCGGGAGAGAACAAGCAGTGTGAAAACACC

GAGGGCGGTTATCGCTGCATCTGTGCCGAGGGCTACAAGCAGATGGAAGGCATCTGTG

TGAACAGAAGACGAGTTGGTGGTGCTGCAGCAGATGTTCTTTGGCATCATCATCTGTG

CACTGGCCACGCTGGCTGCTAAGGGCGACTTGGTGTTCACCGCCATCTTCATTGGGGC

TGTGGCGGCCATGACTGGCTACTGGTTGTCAGAGCGCAGTGACCGTGTGCTGGAGGGC

TTCATCAAGGGCAGATAATCGCGGCCACCACCTGTAGGACCTCCTCCCACCCACGCTG

CCCCCAGAGCTTGGGCTGCCCTCCTGCTGGACACTCAGGACAGCTTGGTTTATTTTTG

AGAGTGGGGTAAGCACCCCTACCTGCCTTACAGAGCAGCCCAGGTACCCAGGCCCGGG

CAGACAAGGCCCCTGGGGTAAAAAGTAGCCCTGAAGGTGGATACCATGAGCTCTTCAC

CTGGCGGGGACTGGCAGGCTTCACAATGTGTGAATTCAAAAGTTTTTCCTTAATGGTG

GCTGCTAGAGCTTTGGCCCCTG

ORF Start: ATG ORF Stop: TAA at 1238 at 29 SEQ ID NO: 136 403 as MW at 42961.2kD

NOV28d, MAPWPPKGLVPAVLWGLSLFLNLPGPIWLQPSPPPQSSPPPQPHPCHTCRGLVDSFNK

PIOtelri SequeriCe ESWWFHKQQEAPDLFQWLCSDSLKLCCPAGTFGPSCLPCPGGTERPCGGYGQCEGEGT

RGGSGHCDCQAGYGGEACGQCGLGYFEAERNASHLVCSACFGPCARCSGPEESNCLQC

KKGWALHHLKCVDCAKACLGCMGAGPGRCKKCSPGYQQVGSKCLVSLLLMDTGTGSPS

MNGEEAGIWAGGGRKGGMLPGQRGGDGQDGVRCWVGGPSRTLTPPSPQDVDECETEVC

PGENKQCENTEGGYRCICAEGYKQMEGICVNRRRVGGAAADVLWHHHLCTGHAGC

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 28B.
Table 28B. Comparison of NOV28a against NOV28b through NOV28d.
NOV28a Residues/Identities/

Protein SequenceMatch ResiduesSimilarities for the Matched Region NOV28b 44..364 307/321 (9S%) 17..336 307/321 (9S%) NOV28c 46..364 286/319 (89%) 19..336 286/319 (89%) NOV28d 1..348 270/384 (70%) 1..381 27S/384 (71%) Further analysis of the NOV28a protein yielded the following properties shown in Table 28C.
Table 28C. Protein Sequence Properties NOV28a PSort 0.6400 probability located in plasma membrane; 0.4600 probability located in analysis: Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane);
0.1000 probability located in endoplasmic reticulum (lumen) SignalP Likely cleavage site between residues 30 and 31 analysis:
A search of the NOV28a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 28D.

Table 28D. Geneseq Results for NOV28a NOV28a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent for Identifier#, Date] Match the Matched Value ResiduesRegion AAU 12316Human PR0214 polypeptide 1..421 418/421 (99%)0.0 sequence - Homo Sapiens, 1..420 418/421 (99%) 420 aa.

[W0200140466-A2, 07-JUN-2001]

AAM41685 Human polypeptide SEQ 1..421 418/421 (99%)0.0 ID NO

6616 - Homo Sapiens, 513 94..513 418/421 (99%) aa.

[W0200153312-A1, 26-JUL-2001]

AAM39899 Human polypeptide SEQ 1..421 418/421 (99%)~0.0 ID NO

3044 - Homo Sapiens, 420 1..420 418/421 (99%)~
aa.

[W0200153312-A1, 26-JUL-2001]

AAB68594 PR0214 - Homo Sapiens, 1..421 418/421 (99%)0.0 420 aa.

[W0200105836-A1, 25-JAN-2001]1..420 418/421 (99%) AAB27228 Human EXMAD-6 SEQ ID NO: 1..421 418/421 (99%)0.0 Homo Sapiens, 420 aa. 1..420 418/421 (99%) [W0200068380-A2, 16-NOV-2000]

In a BLAST search of public sequence databases, the NOV28a protein was found to have homology to the proteins shown in the BLASTP data in Table 28E.
Table 28E. Public BLASTP Results for NOV28a Protein NOV28a Identities/

AccessionProtein/Organism/Length Residues/Similarities for Expect Number Match the Matched Value ResiduesPortion Q9Y409 HYPOTHETICAL 44.9 KDA 1..418 413/418 (98%) 0.0 PROTEIN - Homo Sapiens 1..417 413/418 (98%) (Human), 417 aa.

Q91XD7 UNKNOWN (PROTEIN FOR 1..421 383/421 (90%) 0.0 MGC:18896) - Mus musculus1..420 405/421 (95%) (Mouse), 420 aa.

Q96HD1 UNKNOWN (PROTEIN FOR 1..362 348/362 (96%) 0.0 MGC:8447) - Homo sapiens1..361 353/362 (97%) (Human), 422 aa.

Q9CYA0 5730592L21RIK PROTEIN 33..346 154/316 (48%) e-100 - Mus musculus (Mouse), 350 16..330 200/316 (62%) aa.

Q60438 HT PROTEIN - Cricetulus 9..339 156/333 (46%) 4e-97 griseus (Chinese hamster), 348 3..324 202/333 (59%) aa.

PFam analysis predicts that the NOV28a protein contains the domains shown in the Table 28F.
Table 28F. Domain Analysis of NOV28a Identities/

Pfam Domain NOV28a Match Similarities Expect Region for the Matched Value Region laminin_EGF: 11/60 (18%) 0.11 domain 1 of 168..211 1 32/60 (53%) zf MYND: domain 218..243 10/43 (23%) 4.7 1 of 1 15/43 (35%) PHD: domain 1 217..277 12/64 (19%) 2.8 of 1 38/64 (59%) TIL: domain 1 249..309 17/79 (22%) 8.1 of 1 37/79 (47%) Furin-like: domain189..310 36/188 (19%) 6.5 1 of 1 76/188 (40%) EB: domain 1 292..344 15/62 (24%) 0.3 of 1 35/62 (56%) EXAMPLE 29.

The NOV29 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 29A.
Table 29A. NOV29 Sequence Analysis SEQ ID NO: 137 6997 by NOV29a, ATGGGGTGGAGGGGGCTGATCGCAGCCTTGCCCCTGCTCTCCTTGGTGCAGCCTGCTC

DNA

TTGTGACCAGCTTGCACAGGACATGGCCGAGGAGGCAGCCCAGAACATTTCTGATGAC
SeqlleriCe CAGGAAAGGTGTCTCCAGGCTGCCTGCTGCCTTTCCTTTGGTGGTGAGCTGTCTGTGA

GCACTGACAAGAGCTGGGGTCTTCATCTGTGCAGCTGTAGCCCTCCTGGAGGTGGATT

GTGGGTCGAGGTCTATGCTAATCATGTGCTTCTTATGAGTGATGGGAAGTGTGGCTGT

CCTTGGTGTGCTCTGAATGGAAAGGCAGAAGACCGGGAATCACAGAGCCCATCCTCAT

CAGCTTCCAGGCAGAAGAACATTTGGAAAACAACTAGTGAAGCAGCGTTAAGTGTTGT

TAATGAAAAAACACAGGCTGTTGTTAATGAAAAAACACAGGCGCCTCTGGATTGTGAT

AACAGTGCTGATAGTCTCCGAGTCTTTGCTGACAGCAGTATTGGGGAGAATTGGACCC

TTCAGATGGTTTGTGACCCAGACACTTGGATGCGTGGGCCCAGCTCCCACGGCCTTCC

GCCTGGCATTCCTCGCACCCCCAGCTTCACGGCATCGCAGTCTGGTTCTGAGATCCTC

TATCCCCCTACTCAGCATCCTCCTGTGGCCATCCTAGCTCGAAATTCTGATAACTTCA

TGAACCCTGTTCTTAATTGCTCCCTGGAAGTGGAAGCTCGGGCACCTCCAAATCTGGG

ATTCCGTGTTCATATGGCTTCTGGAGAGGCTCTCTGTCTGATGATGGATTTCGGGGAC

AGTTCTGGGGTTGAAATGAGGCTACACAACATGTCTGAGGCAATGGCGGTGACTGCCT

ACCACCAGTACTCAAAAGAAGGAGTCTATATGCTCAAGGCTGTTATTTATAACGAGTT

TCATGGAACCGAAGTGGAGCTTGGGCCTTATTATGTGGAGATTGGCCATGAGGCCGTG

TCTGCGTTCATGAACTCCAGCAGTGTCCATGAAGATGAAGTGCTTGTCTTTGCTGACT

CCCAAGTGAATCAGAAAACCGTCTCTGTCTACACAAATGGAACTGTGTTTGCCACAGA

CACAGACATTACATTTACAGCTGTTACCAAGGAAACAATACCCCTGGAATTTGAGTGG

TATTTTGGAGAGGATCCACCAGTGAGGACAACTTCAAGAAGCATTAAAAAAAGACTCA
GCATCCCCCAATGGTATCGTGTGATGGTTAAGGCTTCCAACAGGATGAGCAGTGTGGT
CTCTGAGCCCCATGTCATCAGGGTGCAGAAGAAAATTGTGGCCAATCGGCTCACGTCC
CCCTCCTCAGCTCTGGTAAATGCCAGTGTGGCCTTTGAGTGCTGGATCAACTTCGGCA
CAGATGTTGCCTACCTGTGGGACTTTGGGGATGGCACCGTCAGCCTGGGGAGCAGCTC
CAGCAGCCATGTCTACAGTAGGGAAGGAGAATTTACAGTGGAGGTCCTTGCCTTCAAT
AATGTCAGTGCCTCCACTCTAAGACAGCAACTTTTCATCGTGTGCGAGCCCTGCCAGC
CACCCCTGGTGAAGAACATGGGGCCTGGGAAAGTCCAGATATGGAGGTCTCAGCCTGT
GAGGCTGGGAGTGACGTTTGAAGCTGCAGTCTTCTGTGATATTTCCCAAGGTCTTTCT
TACACCTGGAACTTGATGGACTCTGAAGGGCTCCCTGTCTCCCTCCCTGCTGCTGTGG
ACACTCACAGACAGACCCTCATCCTCCCGAGCCACACCTTGGAGTATGGGAACTACAC
TGCCCTTGCCAAGGTTCAGATTGAAGGCAGTGTGGTGTACAGCAACTACTGTGTGGGC
CTGGAGGTGCGAGCCCAGGCCCCTGTCAGTGTGATCTCCGAGGGCACACACCTATTCT
TCTCCAGGACCACCTCATCCCCCATTGTCCTCAGAGGGACCCAGTCCTTCGACCCTGA
CGACCCTGGGGCGACTCTCAGCCACTCCGATGACTTCTCCAACAGGTATCACTGGGAA
TGCGCCACCGCTGGCTCCCCAGCACATCCCTGCTTCGACTCCTCCACTGCACACCAAC
TGGATGCCGCGGCTCCCACTGTTTCCTTTGAGGCACAATGGCTCAGTGACAGCTATGA
TCAGTTCCTTGTGATGCTGAGGGTCTCCAGTGGTGGCCGGAACTCTTCTGAGACCCGG
GTGTTCCTGTCCCCCTACCCTGACTCGGCGTTCAGATTCGTCCACATCTCCTGGGTCA
GCTTTAAAGACACCTTCGTCAACTGGAATGACGAACTCTCTCTTCAAGCTATGTGTGA
GGACTGCAGTGAAATACCGAATCTGTCTTATTCCTGGGATCTCTTTTTAGTCAATGCA
AGGATAGAAGTCCGTGTGAACACTTGTGAGGCACCAGCAGAAGAGG
TGACACACTCAAGGGCTGCTTCTGACCTCAGTGTGATATGGAAGGCTGCGCCCAACAC
CTGTGTAGGCAGTTTTATTGAGCTAAAGCCACAGTTCAGAAGGACCTGCGATGTGACA
CACTGCCCAGAGGGCTGTGTCCGTCACCACCTCGCCTGTCTTTTGGGCCAGCTGCACA
AGTCATCACAGTTAAACCTGCTGCCCACTGAGCCTGGCACTGCAGATCCTGATGCAAC
GACCACACCATTCTCACGGGAACCTTCACCCGTGACCCTTGGCCAACCTGCCACTTCA
GCTCCAAGGGGAACCCCCACAGAGCCCATGACTGGAGTCTACTGGATTCCTCCTGCGG
CCAGAGGAAGGTTCACTAGACCTAGAGCCAGG
TCCCTGATGACTGGCCGCTCTGAGAGAAGTCAGCCCACCCAC
TCAGGACCTAGCT
AACCTGGTGGACCCCTCCCTGTCTGC
AGGCAGAGCCGAGCCTGTCCTCATGATTGACTGGCCCAAGGCCCTGCTGGGTCGAGCA
GTTTTCCAAGGCTATTCATCCTCAGGTATTACAGAACAGACAGTGACAATCAAGCCAT
ACTCTCTGAGCAGTGGAGAGACGTACGTCCTGCAAGTGTCTGTGGCTTCGAAGCATGG
CTTACTGGGTAAAGCTCAGCTGTACTTGACAGTCAACCCGGCTCCTCGGGACATGGCC
TGTCAGGTGCAGCCCCACCATGGTCTGGAAGCACACACCGTCTTCAGTGTCTTCTGCA
TGTCTGGAAAACCGGACTTCCATTATGAATTTAGTTACCAGATAGGAAACACCTCCAA
ACACACTTTGTACCATGGGAGAGACACCCAGTATTATTTTGTGTTGCCAGCTGGTGAG
CACTTGGACAATTACAAAGTCATGGTTTCCACTGAAATCACAGATGGCAAAGGCTCCA
AGGTCCAGCCGTGCACTGTGGTGGTGACTGTGCTGCCCCGCTACCATGGAAATGACTG
TCTGGGCGAGGACCTGTATAATTCCAGCCTGAAAAACCTTTCTACCCTCCAGCTGATG
GGGAGTTACACAGAAATCAGGAACTACATCACTGTGATCACCAGAATCCTGAGTCGTT
TGTCTAAGGAGGACAAAACTGCCTCCTGCAACCAATGGTCACGAATACAGGATGCATT
AATTTCTTCAGTATGCAGATTGGCTTTTGTAGATCAGCTAGGCTTTATGAGTGCGGTT
CTCATCCTCAAGTACACCCGGGCACTCCTTGCTCAAGGCCAGTTCTCGGGGCCATTTG
TGATTGACAAAGGAGTGAGGCTTGAGCTCATCGGTCTCATATCCAGAGTCTGGGAAGT
CTCTGAGCAAGAAAACTCGAAGGAGGAAGTCTATCGACATGAAGAAGGAATTACAGTC
ATCTCAGATTTATTGTTGATTGGTGGAGTTGTGGGCCTCAACCTCTATACCTGCTCCA
GCAGAAGACCCATCAACAGGCAATGGCTAAGGAAACCCGTGATGGTCGAGTTTGGGGA
GGAGGATGGCCTGGATAATAGGAGAAATAAAACGACATTTGTATTACTTCGGGATAAA
GTGAATCTCCATCAGTTCACTGAGCTTTCCGAAAACCCCCAGGAATCTCTACAGATAG
AAATTGAATTTTCCAAACCTGTTACAAGGGCATTTCCCGTCATGTTGCTAGTAAGATT
CTCTGAGAAACCTACTCCCTCTGATTTTCTTGTGAAGCAGATCTACTTCTGGGATGAG
TCAATTGTGCAGATTTATATACCTGCTGCTTCTCAGAAAGATGCCAGTGTAGGCTATT
TATCCTTATTGGATGCTGACTATGACAGAAAACCTCCAAACAGATATTTAGCTAAGGC
TACAGTACATTTCCAGTGGATCCGATGCCTGTTTTGGGACAAGAGAGAG
TGGAAATCTGAACGTTTCTCTCCACAACCAGGGACTTCTCCTGAAAAAGTGAACTGCA
GCTACCATCGCCTCGCGGCATTCGCTCTCCTAAGGAGAAAGCTGAAGGCCAGTTTTGA
ACAGAGCCACCCAGAAAACTTGCTTCCCAGTATTTTT
TTATGGGTTCTGTGATTCTTTATGGATTTTTGGTCGCTAAAAGTAGACAAGTAGATC
Igl ATCATGAAAAAAAGAAAGCTGGTTACATCTTTCTGCAAGAAGCTTCCCTGCCGGGCCA

TCAGCTATATGCGGTCGTCATTGACACTGGCTTCCGAGCTCCGGCCAGCGCTCCTGCC

CAACTGGGCCTGCTGAGGAAGATCCGCCTCTGGCACGACAGCCGTGGGCCTTCCCCAG

GCTGGTTCATCAGCCACGTGATGGTGAAGGAGCTGCACACGGGACAGGGCTGGTTCTT

CCCTGCCCAGTGCTGGCTGTCTGCCGGCAGGCATGATGGTCGCGTGGAGCGGGAGCTC

ACCTGTCTGCAAGGGGGACTCGGCTTCCGGAAGCTTTTCTATTGCAAGTTCACAGAGT

ACCTGGAGGATTTCCATGTCTGGCTGTCGGTGTACAGCAGGCCCTCCTCCAGCCGCTA

CCTGCACACGCCGCGCCTCACCGTGTCCTTCTCCCTGCTGTGCGTCTACGCGTGTCTC

ACTGCCCTGGTTGCTGCTGGAGGGCAAGAGCAGGTGAGAGCCATCGCTTTTCCTTATA

GCAGCTTCCAGATCCGACTACACTGTGGCCCCTTTTTGCCTAAGAAATCAACAAAGCT

CACAGTTCTCCGAGAAAAGTTTAAACCAGGGGAAGCAAGCCTGGCTGCCTGGGGACCA

GAGAAGGAACAGGAGGGCTCTGCCCGGCTCAGCAAGGTACCTGCGACTTGTCCTCATG

GCCCTGTTCTCCTGAGCAGCCCCTTCATTGCTGGGGAACACGCTTGGCGAACCACCTC

TTTCCTTCTGCAGGAAGCCCCGGGGTCTGCCCGAGTGGAGCCACACAGCCCACTTAGA

GGAGGAGCACAGACCGAGGCACCCCATGGTGGGTCAGAAAGAAGGGGTCTCAGCAGAG

GCCTGAAACAGGAAGGAAGTGAAGCCCAGAAGAATTCAGAAAGCCCTGTGTGTCTACT

CAGTAAATACCGGCAGGACCGTGGGAGAGACACTGTGGAGCAGCAAGGCTCGGGCACC

CAGCAGTGGTTTGGAGGGACTAATGCCCCAGTGGTCAAGGGCCCTTCAGCCTTGGTGG

AGCTCTGCAGTGTGGGCCATTTGTGGGACCGCTTCTTTGGCCTGCAGTTTGGGGACAG

GATTTCTAGCCTACAGGTATGCCTCATGGCCTTGGGTTTTGCTTGGAAAAGAAGAGCT

GACAACCACTTTTTTACTGAGTCTTTATGTGAGGCTACCAGGGATCTGGACTCTGAAT

TGGCAGAACGTTCCTGGACTCGCCTCCCCTTCTCTTCAAGCTGCAGTATTCCTGACTG

TGCAGGCGAGGTTGAAAAAGTCTTGGCTGCCCGACAACAAGCTCGCCACCTGCGCTGG

GCGCATCCACCATCCAAGGCCCAGCTGAGGGGCACCAGACAGAGGATGAGGAGAGAGA

GTCGCACACGGGCTGCCCTGAGAGACATTTCCATGGACATCCTCATGCTGCTTCTGCT

TTTGTGTGTAATATATGGGAGATTTTCCCAAGATGAATACTCCCTCAATCAAGCTATC

CGGAAAGAATTTACAAGAAATGCCAGAAACTGCTTGGGTGGCCTGAGAAACATCGCTG

ACTGGTGGGACTGGAGTCTGACCACACTTCTGGATGGCCTGTACCCGGGAGGCACCCC

GTCAGCCCGTGTGCCGGGGGCTCAGCCTGGAGCTCTTGGAGGAAAATGCTACCTAATA

GGCAGTTCCGTAATTAGGCAGCTAAAAGTTTTTCCTAGGCATTTATGCAAGCCTCCCA

GGCCATTTTCAGCACTCATCGAAGACTCTATTCCTACATGTAGTCCCGAAGTTGGAGG

CCCTGAGAACCCCTACCTGATAGACCCAGAGAACCAAAACGTGACCCTGAATGGTCCT

GGGGGCTGTGGGACAAGGGAGGACTGTGTGCTCAGCCTGGGCAGAACAAGGACTGAAG

CCCACACAGCCCTGTCCCGACTCAGGGCCAGCATGTGGATTGACCGCAGCACCAGGGC

TGTGTCTGTGCACTTCACTCTCTATAACCCTCCAACCCAACTCTTCACCAGCGTGTCC

CTGAGAGTGGAGATCCTCCCTACGGGGAGTCTCGTCCCCTCATCCCTGGTGGAGTCAT

TCAGCATCTTCCGCAGCGACTCAGCCCTGCAGTACCACCTCATGCTTCCCCAGGTGAG

CTGACCTGCCTCTTGGGCCTCCTGGAGGTGCACAGGAAGATGGGGCTTCACCTGGGCT

GGGCTTCTCCACCAGACAGGACTAGTTCCCTACCCAT

ORF Start: ATG ORF Stop:
at 1 TGA at SEQ ID NO: 138 2301 as MW at 254558.SkD

NOV29a, MGWRGLIAALPLLSLVQPALGTSSKDEDVGRSWSADCHTCDQLAQDMAEEAAQNISDD

Protein SeC111e11Ce PWCALNGKAEDRESQSPSSSASRQKNIWKTTSEAALSVVNEKTQAVVNEKTQAPLDCD

NSADSLRVFADSSIGENWTLQMVCDPDTWMRGPSSHGLPPGIPRTPSFTASQSGSEIL

YPPTQHPPVAILARNSDNFMNPVLNCSLEVEARAPPNLGFRVHMASGEALCLMMDFGD

SSGVEMRLHNMSEAMAVTAYHQYSKEGVYMLKAVIYNEFHGTEVELGPYYVEIGHEAV

SAFMNSSSVHEDEVLVFADSQVNQKTVSWTNGTVFATDTDITFTAVTKETIPLEFEW

YFGEDPPVRTTSRSIKKRLSIPQWYRVMVKASNRMSSWSEPHVIRVQKKIVANRLTS

PSSALVNASVAFECWINFGTDVAYLWDFGDGTVSLGSSSSSHWSREGEFTVEVLAFN

NVSASTLRQQLFIVCEPCQPPLVKNMGPGKVQIWRSQPVRLGVTFEAAVFCDISQGLS

YTWNLMDSEGLPVSLPAAVDTHRQTLILPSHTLEYGNYTALAKVQIEGSWYSNYCVG

LEVRAQAPVSVISEGTHLFFSRTTSSPIVLRGTQSFDPDDPGATLSHSDDFSNRYHWE

CATAGSPAHPCFDSSTAHQLDAAAPTVSFEAQWLSDSYDQFLVMLRVSSGGRNSSETR

VFLSPYPDSAFRFVHISWVSFKDTFVNWNDELSLQAMCEDCSEIPNLSYSWDLFLVNA

TEKNRIEVRVNTCEAPAEEVTHSRAASDLSVIWKAAPNTCVGSFIELKPQFRRTCDVT

HCPEGCVRHHLACLLGQLHKSSQLNLLPTEPGTADPDATTTPFSREPSPVTLGQPATS

APRGTPTEPMTGVYWIPPAGDSAVLGEAPEEGSLDLEPGPQSKGSLMTGRSERSQPTH

SPDPHLSAKDTSFPGSGPSLSAEESPGDGDNLVDPSLSAGRAEPVLMIDWPKALLGRA

VFQGYSSSGITEQTVTIKPYSLSSGETYVLQVSVASKHGLLGKAQLYLTVNPAPRDMA
CQVQPHHGLEAHTVFSVFCMSGKPDFHYEFSYQIGNTSKHTLYHGRDTQYYFVLPAGE
HLDNYKVMVSTEITDGKGSKVQPCTVWTVLPRYHGNDCLGEDLYNSSLKNLSTLQLM
GSYTEIRNYITVITRILSRLSKEDKTASCNQWSRIQDALISSVCRLAFVDQLGFMSAV
LILKYTRALLAQGQFSGPFVIDKGVRLELIGLISRVWEVSEQENSKEEVYRHEEGITV
ISDLLLIGGWGLNLYTCSSRRPINRQWLRKPVMVEFGEEDGLDNRRNKTTFVLLRDK
VNLHQFTELSENPQESLQIEIEFSKPVTRAFPVMLLVRFSEKPTPSDFLVKQIYFWDE
SIVQIYIPAASQKDASVGYLSLLDADYDRKPPNRYLAKAVNYTVHFQWIRCLFWDKRE
WKSERFSPQPGTSPEKVNCSYHRLAAFALLRRKLKASFEVSDISKLQSHPENLLPSIF
IMGSVILYGFLVAKSRQVDHHEKKKAGYIFLQEASLPGHQLYAWIDTGFRAPASAPA
QLGLLRKIRLWHDSRGPSPGWFISHVMVKELHTGQGWFFPAQCWLSAGRHDGRVEREL
TCLQGGLGFRKLFYCKFTEYLEDFHVWLSVYSRPSSSRYLHTPRLTVSFSLLCVYACL
TALVAAGGQEQVRAIAFPYSSFQIRLHCGPFLPKKSTKLTVLREKFKPGEASLAAWGP
EKEQEGSARLSKVPATCPHGPVLLSSPFIAGEHAWRTTSFLLQEAPGSARVEPHSPLR
GGAQTEAPHGGSERRGLSRGLKQEGSEAQKNSESPVCLLSKYRQDRGRDTVEQQGSGT
QQWFGGTNAPWKGPSALVELCSVGHLWDRFFGLQFGDRISSLQVCLMALGFAWKRRA
DNHFFTESLCEATRDLDSELAERSWTRLPFSSSCSIPDCAGEVEKVLAARQQARHLRW
AHPPSKAQLRGTRQRMRRESRTRAALRDISMDILMLLLLLCVIYGRFSQDEYSLNQAI
RKEFTRNARNCLGGLRNIADWWDWSLTTLLDGLYPGGTPSARVPGAQPGALGGKCYLI
GSSVIRQLKVFPRHLCKPPRPFSALIEDSIPTCSPEVGGPENPYLIDPENQNVTLNGP
GGCGTREDCVLSLGRTRTEAHTALSRLRASMWIDRSTRAVSVHFTLYNPPTQLFTSVS
LRVEILPTGSLVPSSLVESFSIFRSDSALQYHLMLPQVS
Further analysis of the NOV29a protein yielded the following properties shown in Table 29B.
Table 29B. Protein Sequence Properties NOV29a PSort y 0.6400,~probability located in plasma membrane; 0.4600 probability located in analysis: Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane);
0.1000 probability located in endoplasmic reticulum (lumen) SignalP Likely cleavage site between residues 22 and 23 analysis:
A search of the NOV29a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins showwin Table 29C.
Table 29C. Geneseq Results for NOV29a NOV29a Identities/

Geneseq Protein/Organism/I,ength Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value ResiduesRegion AAU14647Novel bone marrow polypeptide196..683487/488 (99%)0.0 #46 -Homo sapiens, 488 aa. 1..488 487/488 (99%) [W0200157187-A2, 09-AUG-2001 ]

AAU29269Human PRO polypeptide sequence2046..2300254/255 (99%)e-147 #246 - Homo sapiens, 300 1..255 255/255 (99%) aa.

[W0200168848-A2, 20-SEP-2001]

AAE03429 e-139 protein HETDB76, SEQ ID 1..240 240/240 (99%) NO: 112 -Homo sapiens, 561 aa.

[W0200132675-A1, 10-MAY-2001]

AAU14741 Novel bone marrow polypeptide478..618 140/141 (99%)Se-79 #140 - Homo Sapiens, 142 aa. 2..142 140/141 (99%) [W0200157187-A2, 09-AUG-2001]

AAB41274 Human ORFX ORF1038 polypeptide1621..1738116/118 (98%)Se-66 sequence SEQ ID N0:2076 43..160 116/118 (98%) - Homo sapiens, 160 aa. [W0200058473-A2, OS-OCT-2000]

' ; In a BLAST search of public sequence databases, the NOV29a protein was found to have homology to the proteins shown in the BLASTP data in Table 29D.
Table 29D. Public BLASTP Results for NOV29a NOV29a Identitiesl Protein Residues/ SimilaritiesExpect for Accession Protein/Organism/LengthMatch the Matched Value Number Residues Portion Q96Q08 KIAA1879 PROTEIN - Homo1449..173477/332 (23%)Se-17 Sapiens (Human), 995 212..538 136/332 (40%) as (fragment).

CAB59175 SEQUENCE 3 FROM PATENT 1621..173745/121 (37%)2e-16 W09518225 - Homo Sapiens403..523 67/121 (55%) (Human), 1614 as (fragment).

CAB59174 SEQUENCE 1 FROM PATENT 1621..173745/121 (37%)2e-16 W09518225 - Homo sapiens3128..324867/121 (55%) (Human), 4339 as (fragment).

042181 PKD1 PROTEIN - Fugu 308..795 120/517 (23%)2e-16 rubripes (Japanese puffe~sh) 2000..2473191/517 (36%) (Takifugu rubripes), 4578 aa.

Q15141 POLYCYSTIC KIDNEY 1621..173745/121 (37%)2e-16 DISEASE 1 PROTEIN - 3161..328167/121 (55%) Homo sapiens (Human), 4292 aa.

PFam analysis predicts that the NOV29a protein contains the domains shown in the Table 29E.
Table 29E. Domain Analysis of NOV29a Identities/
Pfam Domain NOV29a Match Region Similarities Expect Value for the Matched Region PKD: domain 1 of 2 371..454 0.14 50/94 (53%) PKD: domain 2 456..536 24/93 (26%) 3.7e-09 of 2 61/93 (66%) REJ: domain 1 592..710 39/144 (27%) 0.0013 of 1 74/144 (51%) hormone3: domain1221..1233 6/13 (46%) 7.8 1 of 1 13/13 (100%) GPS: domain 1 1497..1544 13/54 (24%) 0.18 of 1 31/54 (57%) PLAT: domain 1623..1684 15/69 (22%) 2e-OS
1 of 1 ~ ~ 46/69 (67%) EXAMPLE 30.
The NOV30 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 30A.
Table 30A. NOV30 Sequence .
SEQ ID NO: 139 3095 by NOV3Oa, CTGGCCAGACCCTGCCTCCAGCCACCGAGGCACATTACCTGGGCCCAACAGATGTCCT

DNA

AAAGCAGCGAATCCCAGCACCTGAAAAATACCCAGGAGGTCCTCGAACCCACTCTGGT

SequeriCe AACTCTCAACCCCTCATCTGCGAGCACGTGGGGCTTGGGGCCACGTTTGTATGTTGGG

GAGGGCCCTGTGTTTTGGGGGAATGCAGCTCCCTTCTGCAGAGATGGGAGGTGGTCAT

GAAGCTGGACCGCAAGGCCTTGGCTCGCGATCCGCCCGCTTCAGCCTCCCAAAGTACT

GGGATTACAAGAGTGAGCCACTGCGCCAGGCCTCAAACATCAATGTTGATACCTGTTT

TCAAAGTACTGGAAGAAGGTAGGGGTAAGGACAAGGAACCGGGAGGAGTGGAGGGCGT

CACTGGGTTTCGGCGTCTGGCAAGCGGTTCAGCTGTCTGCTCCCTAGCAGCCGGCCTT

CGGGTCGGGCGTCTCCGCCGGCTACTGCCGCTTCAGTTCTCCCGGTGTGGCCACGAGT

CGGGTGAGTCTCGGTTCGAAGACACTCAGCCGGGGATGCCAGAGCCTGTGGGCAGCCG

TATCGAACACGCAGGGTATCGTGGCAATCCAGAACGCTTTTCTGAATGGGATAGTTTG

AAAGAAGGGCAGGCGTCTTTGTGGCACGGTAGGAACTGGGATGCACTTTCGCCGCCCA

GAGAGAAATACATAAAATCTATTGAGCGAGCGCTTGTTAATTATATGTGCCTTCTGCT

TATTATATGCCTACAGGTCACAGGAACCTCAAGTATTTCACAGAATGATGCCAAGGAG

CGCAGTTTCTACACCATCCCTCCCGATCAGACCACATCTATTCCAATCTCAGTCTCAA

ACTCTTCCCCTTTTTCAACTCACATTAATGAATTCACTAAGTACCTAGCACTGAGAAT

AAAAAGCGAAAGCAGCATCCGTCTTCTCTACTCTCACACAGCTTACAGTCCACAGCAA

AGCGCAAGTCATCAAACACACCTGGTTGGCAGTGCCCAGATTCGTCAAGTGAGGGTCC

AGGAAAGCTCTTGCCCTCTTGCCCAGCAGCCGCAGTATCTCAACGGATGCCGTGCACC

ATATTCCCTGGATGCTGAAGACATGGCAGACTATGGGTGGCAGTACCAGAGCCAGGAC

CAACGTCAAGGGTATCCCATCTGGGGCAAACTCACTGTGTACCGGGGAGGAGGCTACG

TGGTCCCCTTGTCCAGGACTAGGCAACAAGAGCGAAACTCTGTCCCTGGCAAAAAAAA

GAACACCTGGCTGGACGCCCTGACCAGAGCTGTGTTTGTGGAGTCCACTGTCTACAAC

GCCAACGTCAACCTGTTCTGCATTGTCACGCTGACGCTAGAGACCAGCGCTCTGGGTG

GGTATTTTGAATTTCTTTTCAAGAAATTCATAAATTTCTATCTAACTTTGGGGTCATT

CGTGGTAGCGGCAGAGCTCATCTACTTCCTCTTTCTCCTCTACTACATTGTGGTGCAA

GTGCTTGAATCCAGGAGGCACAGGTTGCACTATTTCTGCAGCAAGTGGAACCTTCTGG

AGCTGGCCATCATCCTGGCCAGCTGGAGCGCCCTGGCGGTGTTTGTGAAGAGGGCTGT

CCTGGCCGAAAGGGACCTCCAGATCATTGAGACTGAGGGCGCTCTACCGAACTTCCAA

GCTGTTCAAGGATCAACTATACAAATGAACAAATTATCCGCCTTCCTGGTACTCCTGT

CCACAGTGAAGCTTTGGCATCTGCTCAGGTTGAATCCCAAAATGAACATGATCACGGC

AGCCCTACGCCGTGCCTGGGGCGACATTTCAGGCTTTATGATTGTCATCCTTACCATG

CTCCTGGCTTACTCCATCGCGGTAAGTATCTGCTTTGGGTGGAAACTCCGTTCCTACA

AAACCCTCTTTGATGCGGCGGAGACGATGGTCAGCCTTCAGCTGGGAATCTTCAACTA

CGAGGAGGTCCTGGACTATAGCCCAGTGCTTGGCTCCTTCCTCATTGGATCCCCACTG

CACCTGGCCACATTTCTGTTTTTTTTTTTTTTTTTTTTTTTGAGATGGAGTATGGCTA

TTGCATCACACAGACAACCTTCATTAAAGGAAGACACCAAGACAGGAGCTGCTCAGGG

GCCACTGGGCACTGCGGTTAGAAAGGGAGCGAGACGCTCTCTCAAAAAAAAAAGAAAG

AAAAAAAATATTCTGGAAGAGGCAGGAGAATCACTTGAATCCGGGAGAGGGAGGTTGC

AGTTCGAAAGGAAGCGAGAGGGAGCGAAAGGCAGAGGCACTATGTGCCGGGGCGTCAG

TCTGCTTGTCAAGAAAAAAATGATGGATGGGAAGAAAAAGATCACACATCAACATCAA

CATATGAAAAGCATGAGAGACAATTTAAAAAAAGAGGACCTCCCCTCACTGCATTTTC

CCTCACCACAACCCCTCACTCCCAAGACTTTCCCAAAAGATCAGGAAACTAAGCCTGA

GAGAAGCCAATGTGAGGACAACGTGGGTCACGGGAGCCGGGAGCGGGCACTTGAAGCG

GGTAGAGCCACAGGAGCCGGTTTGAGTTTTGTCGTAAGGGTCATGAGAGGCGACCGAA

GGATTTTAAGTGTAGGGGAGAAGAAGTTGAGGAGCCGGGATATCATTGGAAGGATCTT

GGAGTCAGTGGCAGGCAAACAAAATTTAGGTAAGGACTCACAGGAAGAGGTGAGGCAG

ATGGAGGAATTATCCAAGAGTGAAGTGCACAGATGGGAAACAGCCCACAGGAACACCG

TTGTGACTGTAGCATGCGGTACAAAGGGCCCTGAGTGCCAGCCTAAGCAACAGAGCAA

GACTCAGTCTCAAAAAP.AACAAACAAAAAAAATCCCTGGGCGTGGTGGCTCATGCCTG

TAATCTCAACACTTTGGGAGAAAAATATATATATTTTTCCCCTTAAATTATCATGTTG

CAGGCCGGGCACAGTGGCTCATGCCTGCAATCCCAGCACTTTGGGAGGCCAAGGCAGG

CGGATCACCTGACGTAAGGAG

OItF Start: ATG ORF
at S2 Stop:
TAA
at SEQ ID NO: 140 969 MW at 108791.3lcD
as NOV3Oa, MSWQRGHSILLMRPLSSSPVQRKQRIPAPEKYPGGPRTHSGNSQPLICEHVGLGATFV

PrOtelri PVFKVLEEGRGKDKEPGGVEGVTGFRRLASGSAVCSLAAGLRVGRLRRLLPLQFSRCG

Se uenCe HESGESRFEDTQPGMPEPVGSRIEHAGYRGNPERFSEWDSLKEGQASLWHGRNWDAI~S

q PPREKYIKSIERALVNYMCLLLIICLQVTGTSSISQNDAKERSFYTIPPDQTTSIPIS

VSNSSPFSTHINEFTKYLALRIKSESSIRLLYSHTAYSPQQSASHQTHLVGSAQIRQV

RVQESSCPLAQQPQYLNGCRAPYSLDAEDMADYGWQYQSQDQRQGYPIWGKLTWRGG

GYWPLSRTRQQERNSVPGKKKNTWLDALTRAVFVESTVYNANVNLFCIVTLTLETSA

LGGYFEFLFKKFINFYLTLGSFWAAELIYFLFLLYYIWQVLESRRHRLHYFCSKWN

LLELAIILASWSALAVFVKRAVLAERDLQIIETEGALPNFQAVQGSTIQMNKLSAFLV

LLSTVKLWHLLRLNPKMNMITAALRRAWGDISGFMIVILTMLLAYSIAVSICFGWKLR

SYKTLFDAAETMVSLQLGIFNYEEVLDYSPVI~GSFLIGSPLHLATFLFFFFFFFLRWS

MAIASHRQPSLKEDTKTGAAQGPLGTAVRKGARRSLKKKRKKKNILEEAGESLESGRG

RLQFERKREGAKGRGTMCRGVSLLVKKKMMDGKKKITHQHQHMKSMRDNLKKEDLPSL

HFPSPQPLTPKTFPKDQETKPERSQCEDNVGHGSRERALEAGRATGAGLSFWRVMRG

DRRILSVGEKKLRSRDIIGRILESVAGKQNLGKDSQEEVRQMEELSKSEVHRWETAHR

NTWTVACGTKGPECQPKQQSKTQSQKKQTKKIPGRGGSCL

Further analysis of the NOV30a protein yielded the following properties shown in Table 30B.
Table 30B. Protein Sequence Properties NOV30a PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3869 probability located in mitochondrial inner membrane; 0.3000 probability located in endoplasmic reticulum (membrane) SignalP No Known Signal Sequence Predicted analysis:
A search of the NOV30a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 30C.

Table 30C. Geneseq Results for NOV30a NOV30a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent for Identifier#, Date] Match the Matched Value Residues Region AAB68450 Amino acid sequence of 15..967 322/1001 e-125 a human (32%) PKD2 polypeptide - Homo 2..961 493/1001 Sapiens, (49%) 968 aa. [US6228591-B1, 2001 ]

AAY78946 Polycystic kidney disease15..967 322/1001 e-125 PKD2 (32%) amino acid sequence - 2..961 493/1001 Homo sapiens, (49%) 968 aa. [US6031088-A, 2000]

AAM51861 Murine polycystic kidney63..967 302/960 (31%)e-116 disease protein 2 - Mus musculus,39..959 467/960 (48%) 966 aa.

[W0200177331-Al, 18-OCT-2001]

AAB68448 Amino acid sequence of 423..967 188/580 (32%)2e-76 an internal fragment of human PKD2 295..859 303/580 (51 - Homo %) sapiens, 866 aa. [US6228591-B1, MAY-2001 ]

AAY70245 Human Polycystin-L protein217..807 164/616 (26%)2e-60 - Homo sapiens, 805 aa. [W0200012046-A2,75..668 289/616 (46%) 09-MAR-2000]

In a BLAST search of public sequence databases, the NOV30a protein was found to have homology to the proteins shown in the BLASTP data in Table 30D.
Table 30D. Public BLASTP Results for NOV30a NOV30a Identities/

Protein Residues/SimilaritiesExpect for Accession Protein/Organism/Length Match the Matched Value Number ResiduesPortion Q13563 Polycystin 2 (Autosomal 15..967 320/1001 e-123 dominant (31%) polycystic kidney disease type 2..961 490/1001 II (47%) protein) (Polycystwin) (R48321) -Homo Sapiens (Human), 968 aa.

035245 Polycystin 2 - Mus musculus63..925 295/917 (32%)e-114 (Mouse), 966 aa. 39..916 454/917 (49%) 602640 polycystic kidney disease 383..967202/611 (33%)6e-92 protein 2 -human, 608 as (fragment). 6..601 321/611 (52%) Q9UP35 POLYCYSTIN-L - Homo Sapiens217..807165/616 (26%)3e-60 (Human), 805 aa. 75..668 290/616 (46%) Q9POL9 3e-60 2-LIKE PROTEIN - Homo Sapiens 75..668 290/616 (46%) (Human), 805 aa.
PFam analysis predicts that the NOV30a protein contains the domains shown in the Table 30E.
Table 30E. Domain Analysis of NOV30a Identities/
Pfam Domain NOV30a Match Region Similarities Expect Value for the Matched Region ion trans: domain 1 of 1 489..688 41/233 (18%) 2.4e-06 139/233 (60%) EXAMPLE 31.
The NOV31 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 31 A.
Table 31A. NOV31 Sequence Analysis SEQ ID NO: 141 2316 by NOV3la, CCTGAGCCTCATTGGGGGGGTCCTCCCCCCACGGGCCGGGCATGCTGCCCCCCGGAAG

CG59623-O1 G~CCCCTCTCCTCGCTCCCCCCAGCGTCCACGCGGAGCATGAACATTGAGGATGGCG
DNA

CGTGCCCGCGGCTCCCCGTGCCCCCCGCTGCCGCCCGGTAGGATGTCCTGGCCCCACG
SequeriCe GGGCATTGCTCTTCCTCTGGCTCTTCTCCCCACCCCTGGGGGCCGGTGGAGGTGGAGT

GGCCGTGACGTCTGCCGCCGGAGGGGGCTCCCCGCCGGCCACCTCCTGCCCCGTGGCC

TGCTCCTGCAGCAACCAGGCCAGCCGGGTGATCTGCACACGGAGAGACCTGGCCGAGG

TCCCAGCCAGCATCCCGGTCAACACGCGGTACCTGAACCTGCAAGAGAACGGCATCCA

GGTGATCCGGACGGACACGTTCAAGCACCTGCGGCACCTGGAGATTCTGCAGCTGAGC

AAGAACCTGGTGCGCAAGATCGAGGTGGGCGCCTTCAACGGGCTGCCCAGCCTCAACA

CGCTGGAGCTTTTTGACAACCGGCTGACCACGGTGCCCACGCAGGCCTTCGAGTACCT

GTCCAAGCTGCGGGAGCTCTGGCTGCGGAACAACCCCATCGAGAGCATCCCCTCCTAC

GCCTTCAACCGCGTGCCCTCGCTGCGGCGCCTGGACCTGGGCGAGCTCAAGCGGCTGG

AATACATCTCGGAGGCGGCCTTCGAGGGGCTGGTCAACCTGCGCTACCTCAACCTGGG

CATGTGCAACCTCAAGGACATCCCCAACCTGACGGCCCTGGTGCGCCTGGAGGAGCTG

GAGCTGTCGGGCAACCGGCTGGACCTGATCCGCCCGGGCTCCTTCCAGGGTCTCACCA

GCCTGCGCAAGCTGTGGCTCATGCACGCCCAGGTAGCCACCATCGAGCGCAACGCCTT

CGACGACCTCAAGTCGCTGGAGGAGCTCAACCTGTCCCACAACAACCTGATGTCGCTG

CCCCACGACCTCTTCACGCCCCTGCACCGCCTCGAGCGCGTGCACCTCAACCACAACC

CCTGGCATTGCAACTGCGACGTGCTCTGGCTGAGCTGGTGGCTCAAGGAGACGGTGCC

CAGCAACACGACGTGCTGCGCCCGCTGTCATGCGCCCGCCGGCCTCAAGGGGCGCTAC

ATTGGGGAGCTGGACCAGTCGCATTTCACCTGCTATGCGCCCGTCATCGTGGAGCCGC

CCACGGACCTCAACGTCACCGAGGGCATGGCTGCCGAGCTCAAATGCCGCACGGGCAC

CTCCATGACCTCCGTCAACTGGCTGACGCCCAACGGCACCCTCATGACCCACGGCTCC

TACCGCGTGCGCATCTCCGTCCTGCATGACGGCACGCTTAACTTCACCAACGTCACCG

TGCAGGACACGGGCCAGTACACGTGCATGGTGACGAACTCAGCCGGCAACACCACCGC

CTCGGCCACGCTCAACGTCTCGGCCGTGGACCCCGTGGCGGCCGGGGGCACCGGCAGC

GGCGGGGGCGGCCCTGGGGGCAGTGGTGGTGTTGGAGGGGGCAGTGGCGGCTACACCT

ACTTCACCACGGTGACCGTGGAGACCCTGGAGACGCAGCCCGGAGAGGAGGCCCTGCA

GCCGCGGGGGACGGAGAAGGAACCGCCAGGGCCCACGACAGACGGTGTCTGGGGTGGG

GGCCGGCCTGGGGACGCGGCCGGCCCTGCCTCGTCTTCTACCACGGCACCCGCCCCGC

GCTCCTCGCGGCCCACGGAGAAGGCGTTCACGGTGCCCATCACGGATGTGACGGAGAA

CGCCCTCAAGGACCTGGACGACGTCATGAAGACCACCAAAATCATCATCGGCTGCTTC

GTGGCCATCACGTTCATGGCCGCGGTGATGCTCGTGGCCTTCTACAAGCTGCGCAAGC

AGCACCAGCTCCACAAGCACCACGGGCCCACGCGCACCGTGGAGATCATCAACGTGGA

GGACGAGCTGCCCGCCGCCTCGGCCGTGTCCGTGGCCGCCGCGGCCGCCGTGGCCAGT
GGGGGTGGTGTGGGCGGGGACAGCCACCTGGCCCTGCCCGCCCTGGAGCGAGACCACC
TCAACCACCACCACTACGTGGCTGCCGCCTTCAAGGCGCACTACAGCAGCAACCCCAG
CGGCGGGGGCTGCGGGGGCAAAGGCCCGCCTGGCCTCAACTCCATCCACGAACCTCTG
CTCTTCAAGAGCGGCTCCAAGGAGAACGTGCAAGAGACGCAGATCTGAGGCGGCGGGG
CCGGGCGGGCGAGGGGCGTGGAGCCCCCCACCCAGGTCCCAGCCCGGGCGCAGC
ORF Start: ATG at 111 ORF Stop: TGA at 2250 SEQ ID NO: 142 713 as MW at 76433.OkD
NOV3la, MARARGSPCPPLPPGRMSWPHGALLFLWLFSPPLGAGGGGVAVTSAAGGGSPPATSCP
CGS9623-O1 PrOtelri VACSCSNQASRVICTRRDLAEVPASIPVNTRYLNLQENGIQVIRTDTFKHLRHLEILQ
LSKNLVRKIEVGAFNGLPSLNTLELFDNRLTTVPTQAFEYLSKLRELWLRNNPIESIP
SequeriCe SyAFNRVPSLRRLDLGELKRLEYISEAAFEGLVNLRYLNLGMCNLKDIPNLTALVRLE
ELELSGNRLDLIRPGSFQGLTSLRKLWLMHAQVATIERNAFDDLKSLEELNLSHNNLM
SLPHDLFTPLHRLERVHLNHNPWHCNCDVLWLSWWLKETVPSNTTCCARCHAPAGLKG
RYIGELDQSHFTCYAPVIVEPPTDLNVTEGMAAELKCRTGTSMTSVNWLTPNGTLMTH
GSYRVRISVLHDGTLNFTNVTVQDTGQYTCMVTNSAGNTTASATLNVSAVDPVAAGGT
GSGGGGPGGSGGVGGGSGGYTYFTTVTVETLETQPGEEALQPRGTEKEPPGPTTDGVW
GGGRPGDAAGPASSSTTAPAPRSSRPTEKAFTVPITDVTENALKDLDDVMKTTKIIIG
CFVAITFMAAVMLVAFYKLRKQHQLHKHHGPTRTVEIINVEDELPAASAVSVAAAAAV
ASGGGVGGDSHLALPALERDHLNHHHYVAAAFKAHYSSNPSGGGCGGKGPPGLNSIHE
PLLFKSGSKENVQETQI
Further analysis of the NOV3la protein yielded the following properties shown in Table 31B.
Table 31B. Protein Sequence Properties NOV3la PSort 0.7000 probability located in plasma membrane; 0.3000 probability located in analysis: microbody (peroxisome); 0.2000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondria) inner membrane SignalP Likely cleavage site between residues 38 and 39 analysis:
A search of the NOV3la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 31C.
Table 31C. Geneseq Results for NOV3la NOV3la Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate) Match the MatchedValue Residues Region AAE13006 Human leucine-rich repeat1..713 712/713 0.0 (LRR) (99%) family member protein 1..713 712/713 - Homo (99%) Sapiens, 713 aa. [W0200175105-A2, 11-OCT-2001 ]

AAU12355 Human PR0331 polypeptide 54..713 406/660 0.0 sequence (61%) - Homo Sapiens, 640 aa. 44..640 485/660 (72%) [W0200140466-A2, 07-JCTN-2001 AAU00826 Human immune response protein 406/660 (61 0.0 54..713 %) PR0331 (UNQ292) - Homo sapiens, 485/660 (72%) 44..640 640 aa. [W0200119991-A1, 22-MAR-2001 ]

AAB53089 Human angiogenesis-associated 406/660 (61%)0.0 54..713 protein PR0331, SEQ ID N0:137 485/660 (72%) - 44..640 Homo sapiens, 640 aa.

[W0200053753-A2, 14-SEP-2000]

AAB65292 Human PR0331 protein sequence 406/660 (61 0.0 54..713 %) SEQ ID NO:501 - Homo Sapiens, 485/660 (72%) 640 44..640 aa. [W0200073454-A1, 07-DEC-2000]

In a BLAST search of public sequence databases, the NOV3la protein was found to have homology to the proteins shown in the BLASTP data in Table 31 D.
Table 31D. Public BLASTP
Results for NOV3la NOV3la Identities/

Protein Residues/Similarities Expect for AccessionProtein/Organism/Length Match the Matched Value Number ResiduesPortion CAD10322 SEQUENCE 1 FROM PATENT 1..713 712/713 (99%)0.0 W00175105 - Homo sapiens1..713 712/713 (99%) (Human), 713 aa.

Q9NT99 HYPOTHETICAL 45.1 KDA 216..637422/422 (100%)0.0 PROTEIN - Homo sapiens 1..422 422/422 (100%) (Human), 422 as (fragment).

T46266 hypothetical protein 216..636421/421 (100%)0.0 DKFZp761A179.1 - human, 1..421 421/421 (100%) 421 as (fragment).

Q9HCJ2 ICIAA1580 PROTEIN - Homo54..713 406/660 (61%)0.0 Sapiens (Human), 640 44..640 485/660 (72%) as (fragment).

Q9HBW1 BRAIN TUMOR ASSOCIATED 42..713 381/672 (56%)0.0 PROTEIN NAG14 - Homo 34..653 475/672 (69%) Sapiens (Human), 653 aa.

PFam analysis predicts that tein the domains in the NOV3la pro containsshown the Table 31 E.
Table 31E. Domain Analysis of NOV3la Identities/
Pfam Domain NOV3la Match Region Similarities Expect Value for the Matched Region LRRNT: domain 1 56..85 13/31 (42%) 4.8e-06 of 1 21/31 (68%) LRR: domain 1 of 87..110 6/25 (24%) 1.1 18/25 (72%) LRR: domain 2 of 111..134 9/25 (36%) 0.38 17/25 (68%) LRR: domain 3 of 135..158 8/25 (32%) 0.074 19/25 (76%) LRR: domain 4 of 159..182 10/25 (40%) 0.013 18/25 (72%) LRR: domain 5 of 183..207 7/26 (27%) 42 19/26 (73%) LRR: domain 6 of 208..229 8/25 (32%) 1.5 17/25 (68%) LRR: domain 7 of 230..253 12/25 (48%) 0.0068 20/25 (80%) LRR: domain 8 of 254..277 5/25 (20%) 70 16/25 (64%) LRR: domain 9 of 278..301 14/25 (56%) 0.00088 20/25 (80%) LRRCT: domain 1 311..362 19/54 (35%) 6.2e-05 of 1 36/54 (67%) ig: domain 1 of 378..438 15/65 (23%) 2.2e-07 ______ 41/65 (63%) EXAMPLE 32.
The NOV32 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 32A.
Table 32A. NOV32 Sequence Analysis SEQ ID NO: 143 1206 by NOV32a, AAACTGACCACAAAAGGGCTAACGGAATTTTTAGGGGATGATAAATATGTTCAACATC

DNA

AGATATTAATGTGCCAGGCAGTGCTGGCAGGTGAAGCCCCGAGTGGACCCTGTAGATC

SequeriCe GGATGGAGACCACGTGGAGTACCACTACAGCAAGGCCATGCCACTCATCTTCATGAGC

AGTATGCTCTGCAGCGGCACCATGCTGATACTCACTGGGCTGGATGCCCACCTTGAGG

TGCACCGCAGCAAGGAGACGCACATCATCCCTTGTGTGCTGGCCATGCACCAGGCCTG

GTCCAAGTCTGGCCACAAGAAACTACAGCTGGACAAGGCGGGCGTGACTGACGAGGTG

CTGGACATTGCCATGCAGGCCTTCATCCTGGAGGTGATCTCTAAGCAAAGGGAGCCAG

CCCATGTGCTCTCCAACAAGGACCACTTCAGACTCAAGTCCCTTGAATCACTGGTCTA

CCTGTCACACCTGTTCTCCAGCTCCAAGTTCCTGCTTATGGCTCAGGACAGCCATGTC

TCCATGCACTCCTTGATCACATGCAAGGTCACTATTGCAGGCTTCGACCTCAGCAGCT

ATGGCAACTGCCTCACCAAGTGGAACAAGGCCATAGAGGTGATGTACACCCAGTGCAT

GGAGGTGGGCAAGGACAAGTGCCTGCTCGTGTACTACAAGGAACTGGTGCTGCCTAGG

AGCTTCCTCAGACTCATCCCAGACCATCTCGGCATCACCTGGAGCAACACTGTCCTCC

ACCATCAAGACCTCACTGGCAAGTGGAATGGCATCTCCCTGTCTAAGATCCAGTGGTC

CATGGATGAGGTCATCAAGCCTGTGAACCTGGAAGTGCTCTCCAAGTGGACTCACCAC

ATCCCTGGGGACATGGTGCCAGACATGGCCCAGATTGTCCCATGCTGGCTCAGCTTAG

CCATGACCCCTATGCAAATACCCTCCCCAACCCCCACTTCCACTATAGCAACCCTGAC

CCCCATCATCATCAGTAACGCACACCAAGTAAGGGACTATAAAACACCAGTCAATCTG

AAAGGATATTTTCAGGTGAACCAGAATAGCACCTCCTCCCACTTAGGAAGCTCATGAT

TTCCAGATCTCTGCAAATGGCTTTGTTGCCCAAAAGAGAAGAAACT

ORF Start: ATG ORF Stop:
at 38 TGA
at 1157 SEQ ID NO: 144 373 as MW at 41568.3kD

NOV32a, MINMFNILTMVAGCALALVMWQLGQQILMCQAVLAGEAPSGPCRSDGDHVEYHYSKA

PIOtelri AGVTDEVLDIAMQAFILEVISKQREPAHVLSNKDHFRLKSLESLVYLSHLFSSSKFLL
Sequence MAQDSHVSMHSLITCKVTIAGFDLSSYGNCLTKWNKAIEVMYTQCMEVGKDKCLLVYY

KELVLPRSFLRLIPDHLGITWSNTVLHHQDLTGKWNGISLSKIQWSMDEVIKPVNLEV

LSKWTHHIPGDMVPDMAQIVPCWLSLAMTPMQIPSPTPTSTIATLTPIIISNAHQVRD

YKTPVNLKGYFQVNQNSTSSHLGSS

Further analysis of the NOV32a protein yielded the following properties shown in Table 32B.
Table 32B. Protein Sequence Properties NOV32a PSort 0.4600 probability located in plasma membrane; 0.1279 probability located in analysis: microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen) SignalP Likely cleavage site between residues 28 and 29 analysis:
A search of the NOV32a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 32C.
Table 32C. Geneseq Results for NOV32a NOV32a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for Identifier Date] Match the Matched Value ResiduesRegion AAM93565 Human polypeptide, SEQ 10..373 240/376 (63%)e-123 ID NO:

3341 - Homo sapiens, 377 aa. 10..377 273/376 (71%) [EP 1130094-A2, 05-SEP-2001 ]

AAM93219 Human polypeptide, SEQ 10..373 240/376 (63%)e-123 ID NO:

2626 - Homo sapiens, 377 aa. 10..377 273/376 (71 %) [EP1130094-A2, 05-SEP-2001]

AAY69421 Amino acid sequence of 10..373 240/376 (63%)e-123 human TPST-2 polypeptide - Homo Sapiens,10..377 273/376 (71%) 377 aa. [W09965712-A2, 23-DEC-1999]

AAY84306 A human tyrosylprotein 10..373 240/376 (63%)e-123 sulfotransferase 2 (TPST-2)10..377 273/376 (71%) polypeptide - Homo sapiens, 377 aa.

[W0200014250-A1, 16-MAR-2000]

AAY06625 Human tyrosylprotein sulfotransferase10..373 240/376 (63%)e-123 TPST-2 - Homo sapiens, 10..377 273/376 (71%) 377 aa.

[W09938980-A2, OS-AUG-1999]

In a BLAST search of public sequence databases, the NOV32a protein was found to have homology to the proteins shown in the BLASTP data in Table 32D.
Table 32D. Public BLASTP
Results for NOV32a ' NOV32a Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched Value Number ResiduesPortion 060704 Protein-tyrosine sulfotransferase10..373 240/376 (63%)e-122 2 (EC

2.8.2.20) (Tyrosylprotein 10..377 273/376 (71%) sulfotransferase-2) (TPST-2) - Homo sapiens (Human), 377 aa.

088856 Protein-tyrosine sulfotransferase10..373 237/375 (63%)e-121 2 (EC

2.8.2.20) (Tyrosylprotein 10..376 270/375 (71%) sulfotransferase-2) (TPST-2) - Mus musculus (Mouse), 376 aa.

070281 Protein-tyrosine sulfotransferase10..324 159/326 (48%)2e-78 1 (EC

2.8.2.20) (Tyrosylprotein 10..332 213/326 (64%) sulfotransferase-1) (TPST-1) - Mus musculus (Mouse), 370 aa.

060507 Protein-tyrosine sulfotransferase10..363 168/369 (45%)2e-78 1 (EC

2.8.2.20) (Tyrosylprotein 10..368 226/369 (60%) sulfotransferase-1) (TPST-1) - Homo sapiens (Human), 370 aa.

Q9VYB7 Probable protein-tyrosine 46..324 131/280 (46%)Se-68 sulfotransferase (EC 2.8.2.20)57..333 182/280 (64%) (Tyrosylprotein sulfotransferase) (TPST) - Drosophila melanogaster (Fruit fly), 385 aa.

PFam in contains analysis the predicts domains that shown the in the NOV32a prote Table 32E.
Table 32E. Domain Analysis of NOV32a Pfam Domain NOV32a Match Identities/ Expect Region Value for the Matched Region Sulfotransfer: 36..313 38/311 (12%) 7.9 domain 1 of 1 1 SO/311 (48%) EXAMPLE 33.
The NOV33 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 33A.
Table 33A. NOV33 Sequence Analysis SEQ ID NO: 14S 1240 by NOV33a, ACCAAGGACCCCAGAGGATGGAGGCCTCTCGGTGGTGGCTGCTGGTCACTGTGCTCAT

DNA

GGCCCCCAGGACAGCAGCCCTGGGCCTGCCCTGCCCTGCCACAAAATCTCTGTGAGCA
SequeriCe ACATAGACTTTGCCTTCAAGCTCTACAGACAGTTGGCTTTGAACGCCCCCGGGGAGAA

CATTCTCTTCTCCCCAGTGAGCATCTCCCTGGCCTTGGCCATGCTTTCTTGGGGGGCC

CCAGTGGCCAGCAGGACCCAACTCCTGGAGGGCCTGGGGTTCACCCTCACCGTGGTGC

CTGAGGAGGAGATCCAGGAAGGCTTCTGGGATCTGCTGATCAGGCTCCGTGGGCAGGG

TCCCCGGCTCCTCCTGACCATGGACCAGCGCAGGTTCAGCGGCCTGGGCGCGAGGGCC

AACCAGAGCCTAGAGGAGGCCCAAAAACACATTGACGAATATACAGAGCAGCAGACCC

AGGGGAAGCTCGGGGCCTGGGAGAAGGACCTCGGCAGTGAAACCACAGCGGTTCTGGT

GAATCACATGCTCCTCAGAGCTGAGTGGATGAAGCCCTTTGACTCACGTGCCACCAGC

CCAAAGGAGTTCTTTGTAGATGAGCACAGCGCTGTGTGGGTGCCCATGATGAAGGAGA

AGGCCAGCCACCGCTTCCTGCACGACCGTGAGCTGCAATGCTCTGTGCTGCGGATGGA

CCACGCTGGGAACACCACCACCTTCTTCATCTTCCCCAACAGGGGCAAGATGAGGCAG

CTGGAAGATGCCCTGCTGCCTGAAACACTGATTAAGTGGGACAGTCTGCTCAGGCTCG

ATTTCCACTTCCCCAAATTTTCCATTTCTAGAACCTGCAGACTGGAGATGCTCCTCCC

AAAAGTGACTGTGGGTGGAGGCTTCCCTGGGCAGCCTGGACTGAACATTTCTAAAGTA

AGTTGGGGATGGTGTGTTCAGAGGGCCTCTCATAAGGCCATGATGACGCTGGATGAGA

GGGGCTCTGAAGCTGCTGCAGCCACCAGCATTCAGCTCACCCCTGGGCCTCGCCCAGA

CCTTGACTTCCCACCCACTCTGGGCACTGAGTTCAGTCGGCCCTTCCTGGTGATGACT

TTCCACACGGAAACAGGAAGCATGCTTTTTCTGGAGAAGATTGTAAACCCACTGGGAT

AACGCCCCCTCAGACATGCTGG

ORF Start: ATG ORF Stop:
at 18 TAA
at 1218 SEQ ID NO: 146 400 as MW at 44726.OkD

NOV33a, MEASRWWLLVTVLMAGAHCVALVDQEASDLIHSGPQDSSPGPALPCHKISVSNIDFAF

CGS943O-O1 ~'YRQLALNAPGENILFSPVSISLALAMLSWGAPVASRTQLLEGLGFTLTWPEEEIQ

PrOteln Se uenCe EGFWDLLIRLRGQGPRLLLTMDQRRFSGLGARANQSLEEAQKHIDEYTEQQTQGKLGA

q WEKDLGSETTAVLVNHMLLRAEWMKPFDSRATSPKEFFVDEHSAVWVPMMKEKASHRF

LHDRELQCSVLRMDHAGNTTTFFIFPNRGKMRQLEDALLPETLIKWDSLLRLDFHFPK

FSISRTCRLEMLLPKVTVGGGFPGQPGLNISKVSWGWCVQRASHKAMMTLDERGSEAA

AATSIQLTPGPRPDLDFPPTLGTEFSRPFLVMTFHTETGSMLFLEKIVNPLG

Further analysis of the NOV33a protein yielded the following properties shown in Table 33B.
Table 33B. Protein Sequence Properties NOV33a PSort 0.4600 probability located in plasma membrane; 0.1700 probability located in analysis: microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen) SignalP ( Likely cleavage site between residues 20 and 21 analysis:
A search of the NOV33a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 33C.
Table 33C. Geneseq Results for NOV33a NOV33a Identities/

Geneseq Protein/Organism/Length [Patent SimilaritiesExpect #, Residues/ for IdentifierDate] Match the Matched Value Residues Region AAB68434Amino acid sequence of human serpin352/400 (88%)0.0 1..400 protease Zserpl l - Homo Sapiens, 356/400 (89%) 366 1..366 aa. [W0200138534-A2, 31-MAY-2001 ]

AA013910Human polypeptide SEQ ID NO 7..399164/431 (38%)4e-67 27802 - Homo Sapiens, 495 aa. 80..493234/431 (54%) [W0200164835-A2, 07-SEP-2001]

AAG73736Human colon cancer antigen protein164/431 (38%)4e-67 7..399 SEQ ID N0:4500 - Homo Sapiens, 234/431 (54%) 31..444 446 aa. [W0200122920-A2, OS-APR-2001 ]

AAY28643Human serine protease inhibitor 164/431 (38%)4e-67 from 7..399 cDNA clone HETDK50 - Homo 7..420 234/431 (54%) Sapiens, 422 aa. [W09940183-A1, AUG-1999]

AAB74691Human protease and protease inhibitor163/431 (37%)1 e-66 7..399 PPIM-24 - Homo Sapiens, 422 aa. 233/431 (53%) 7..420 [W0200110903-A2, 15-FEB-2001 ]

In a BLAST search of public sequence databases, the NOV33a protein was found to have homology to the proteins shown in the BLASTP data in Table 33D.
Table 33D.
Public BLASTP
Results for NOV33a NOV33a Identities/

Protein Residues/ SimilaritiesExpect for AccessionProtein/Organism/Length the Matched Value Match Number Residues Portion CAC42686 SEQUENCE 1 FROM PATENT 1..400 352/400 (88%)0.0 W00138534 - Homo Sapiens 1..366 356/400 (89%) (Human), 366 aa.

Q96BZ5 Se-66 PROTEIN - Homo sapiens 9..424 235/423 (55%) (Human), 427 aa.

P29622 Kallistatin precursor 8..398 161/423 (38%)1e-65 (Kallikrein inhibitor) (Protease inhibitor9..424 235/423 (55%) 4) -Homo Sapiens (Human), 427 aa.

P05544 Contrapsin-like protease 12..398 151/412 (36%)3e-60 inhibitor 3 precursor (CPI-23) (Serine9..412 222/412 (53%) protease inhibitor 1 ) (SPI-1 ) - Rattus norvegicus (Rat), 413 aa.

S08102 serine proteinase inhibitor36..398 145/388 (37%)4e-60 1 - rat, 403 aa. 22..402 213/388 (54%) PFam analysis predicts that the NOV33a protein contains the domains shown in the Table 33E.
Table 33E. Domain Analysis of NOV33a Identities/

Pfam Domain NOV33a Match RegionSimilarities Expect Value for the Matched Region serpin: domain46..137 48/93 (52%) 8.9e-31 1 of 3 74/93 (80%) serpin: domain154..306 68/168 (40%) 6.5e-34 2 of 3 105/168 (62%) serpin: domain332..398 31/71 (44%) 1.1e-14 3 of 3 53/71 (75%) EXAMPLE 34.

The NOV34 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 34A.
Table 34A. NOV34 Sequence Analysis SEQ ID NO: 147 ~ 1026 by NOV34a, ATGCCACAGCCCAGGGGAGGCCAGCCTGCCTGGCAGCTGACACCCAGCCCTCCCCCCA
CGS93OS-Ol DNA GCTCCCGGATAATGAGCACCCATGTGGCAGGCCTGGGCCTGGACAAGATGAAGCTGGG
CAATCCCCAGTCCTTCCTGGACCAGGAGGAGGCAGATGACCAGCAGCTGCTGGAACCA
SeqLleriCe GAGGCGTGGAAGACCTACACCGAGCGCCGCAATGCCCTGCGTGAGTTCCTGACCTCGG
CTCCTACTACATCGAGGTCCTGCCCAAGCACCTGGCCCTGGGCGACCAGAACCCGCTG
GTGCTGCCTAGCGCCTTGTTCCAGCTCATCGACCCCTGGAAGTTCCAGCGCATGAAGA
AGGTGGGCACAGCTCAGACCAAGATCCAGCTCCTGCTGCTCGGGGACCTGTTGGAACA
GCTCGACCATGGCCGTGCTGAGCTGGATGCCCTGCTCCGGTCGCCAGACCCACGGCCC
TTCCTGGCCGACTGGGCGCTGGTGGAGCGGCGGCTGGCGGACGTGTCGGCCGTCATGG
ACAGCTTCCTGACCATGATGGTGCCGGGGCGGCTACACGTCAAGCACCGCCTGGTGTC
TGATGTCAGTGCCACCAAGATCCCGCACATCTGGCTCATGCTGAGCACCAAGATGCCT
GTCGTGTTTGACCGAAAGGCGTCGGCGGCTCACCAGGACTGGGCCCGGCTGCGCTGGT
TCGTCACCATCCAGCCAGCCACATCGGAGCAGTATGAGTTGCGCTTCAGGCTGCTGGA
CCCGCGGACACAGCAGGAGTGCGCCCAGTGTGGCGTCATCCCCGTGGCTGCCTGCACC

TTCGACGTCCGAAACCTGCTGCCCAACCGATCCTATAAGTTCACCATCAAGAGGGCCG

AGACCTCCACGCTGGTGTACGAGCCCTGGAGGGACAGCCTCACCCTGCACACCAAGCC

GGAGCCCCTGGAGGGGCCCGCCCTCAGCCACTCTGTCTGA

OIRF Start: ATG OIRF
at 1 Stop:
TGA
at 1024 SEQ ID NO: 148 341 as MW at 38993.71cD

NOV34a, MPQPRGGQPAWQLTPSPPPSSRIMSTHVAGLGLDKMKLGNPQSFLDQEEADDQQLLEP

PrOteln VLPSALFQLIDPWKFQRMKKVGTAQTKIQLLLLGDLLEQLDHGRAELDALLRSPDPRP
SeqllenCe FLADWALVERRLADVSAVMDSFLTMMVPGRLHVKHRLVSDVSATKIPHIWLMLSTKMP

WFDRKASAAHQDWARLRWFVTIQPATSEQYELRFRLLDPRTQQECAQCGVIPVAACT

FDVRNLLPNRSYKFTIKRAETSTLVYEPWRDSLTLHTKPEPLEGPALSHSV

SEQ ID NO:' 149 1026 by NOV34b, ATGCCACAGCCCAGGGGAGGCCAGCCTGCCTGGCAGCTGACACCCAGCCCTCCCCCCA

DNA

CAATCCCCAGTCCTTCCTGGACCAGGAGGAGGCAGATGACCAGCAGCTGCTGGAACCA
SequeriCe GAGGCGTGGAAGACCTACACCGAGCGCCGCAATGCCCTGCGTGAGTTCCTGACCTCGG

ACCTGAGTCCGCACCTGCTCAAGCGCCACCACGCCCGCATGCAGCTGCTGCGTAAGTG

CTCCTACTACATCGAGGTCCTGCCCAAGCACCTGGCCCTGGGCGACCAGAACCCGCTG

GTGCTGCCTAGCGCCTTGTTCCAGCTCATCGACCCCTGGAAGTTCCAGCGCATGAAGA

AGGTGGGCACAGCTCAGACCAAGATCCAGCTCCTGCTGCTCGGGGACCTGTTGGAACA

GCTCGACCATGGCCGTGCTGAGCTGGATGCCCTGCTCCGGTCGCCAGACCCACGGCCC

TTCCTGGCCGACTGGGCGCTGGTGGAGCGGCGGCTGGCGGACGTGTCGGCCGTCATGG

ACAGCTTCCTGACCATGATGGTGCCGGGGCGGCTACACGTCAAGCACCGCCTGGTGTC

TGATGTCAGTGCCACCAAGATCCCGCACATCTGGCTCATGCTGAGCACCAAGATGCCT

GTCGTGTTTGACCGAAAGGCGTCGGCGGCTCACCAGGACTGGGCCCGGCTGCGCTGGT

TCGTCACCATCCAGCCAGCCACATCGGAGCAGTATGAGTTGCGCTTCAGGCTGCTGGA

CCCGCGGACACAGCAGGAGTGCGCCCAGTGTGGCGTCATCCCCGTGGCTGCCTGCACC

TTCGACGTCCGAAACCTGCTGCCCAACCGATCCTATAAGTTCACCATCAAGAGGGCCG

AGACCTCCACGCTGGTGTACGAGCCCTGGAGGGACAGCCTCACCCTGCACACCAAGCC

GGAGCCCCTGGAGGGGCCCGCCCTCAGCCACTCTGTCTGA

012F Start: ATG ORF Stop:
at 1 TGA
at 1024 SEQ ID NO: 1S0 341 as MW at 38993.7kD

NOV34b, MPQPRGGQPAWQLTPSPPPSSRIMSTHVAGLGLDKMKLGNPQSFLDQEEADDQQLLEP

PrOtelri Se ueriCe ~'PSALFQLIDPWKFQRMKKVGTAQTKIQLLLLGDLLEQLDHGRAELDALLRSPDPRP

q FLADWALVERRLADVSAVMDSFLTMMVPGRLHVKHRLVSDVSATKIPHIWLMLSTKMP

WFDRKASAAHQDWARLRWFVTIQPATSEQYELRFRLLDPRTQQECAQCGVIPVAACT

FDVRNLLPNRSYKFTIKRAETSTLVYEPWRDSLTLHTKPEPLEGPALSHSV

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 34B.
Table 34B. Comparison of NOV34a against NOV34b and NOV34c.
Protein Sequence NOV34a Residues/ Identities/
Match Residues Similarities for the Matched Region NOV34b 1..341 328/341 (96%) 1..341 328/341 (96%) Further analysis of the NOV34a protein yielded the following properties shown in Table 34C.

Table 34C.
Protein Sequence Properties NOV34a PSort 0.4500 probability located in cytoplasm; 0.4466 probability located in microbody analysis:(peroxisome); 0.2245 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space SignalP No Known Signal Sequence Predicted analysis:

A search of the NOV34a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 34D.
Table 34D. Geneseq Results for NOV34a NOV34a Identities/
Geneseq Protein/Organism/Length Residues/ Expect Identifier [Patent #, Date] Match Similarities for the Value Residues Matched Region No Significant Matches Found In a BLAST search of public sequence databases, the NOV34a protein was found to have homology to the proteins shown in the BLASTP data in Table 34E.
Table 34E. Public BLASTP Results for NOV34a NOV34a Identities/

Protein Residues/ Similarities Expect for AccessionProtein/Organism/LengthMatch the Matched Value Number Residues Portion Q9BW2 HYPOTHETICAL 36.5 KDA 24..341 318/318 (100%)0.0 PROTEIN - Homo sapiens1..318 318/318 (100%) (Human), 318 aa.

Q9D9W3 1700026M20RIK PROTEIN 66..173 89/108 (82%) 6e-46 -Mus musculus (Mouse), 2..109 96/108 (88%) 163 aa.

PFam analysis predicts that the domains in the the NOV34a protein shown contains Table 34F.
Table 34F. Domain Analysis of NOV34a Identities/
Pfam Domain NOV34a Match Region Similarities Expect Value for the Matched Region fn3: domain 1 of 1 231..312 10/87 (11%) 5.9 52/87 (60%) EXAMPLE 35.
The NOV3S clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 35A.
Table 35A. NOV35 Sequence Analysis SEQ ID NO: 1 S 1 1610 by NOV3Sa, CGTCTTCGGGACGCGCCCGCTCTTCGCCTTTCGCTGCAGTCCGTCGATTTCTTTCTCC

DNA

GTCAACCTGCCCTTGGTGAGCTCCACGTATGACCTCATGTCCTCAGCCTATCTCAGTA

SequeriCe CAAAGGACCAGTATCCCTACCTGAAGTCTGTGTGTGAGATGNCAGAGAACGGTGTGAA

GACCATCACCTCCGTGGCCATGACCAGTGCTCTGCCCATCATCCAGAAGCTAGAGCCG

CAAATTGCAGTTGCCGATACCTATGCCTGTAAGGGGCTAGACAGGATTGAGGAGAGAC

TGCCTATTCTGAATCAGCCATCAACTCAGATTGTTGCCAATGCCAAAGGCGCTGTGAC

TGGGGCAAAAGATGCTGTGACGACTACTGTGACTGGGGCCAAGGATTCTGTNGCCAGC

ACGATCACAGGGGTGATGGACAAGACCAAAGGGGCAGTGACTGGCAGTGTGGAGAAGA

CCAAGTCTGTGGTCAGTGGCAGCATTAACACAGTCTTGGGGAGTCGGATGATGCAGCT

CGTGAGCAGTGGCGTAGAAAATGCACTCACCAAATCAGAGCTGTTGGTAGAACAGTAC

CTCCCTCTCACTGAGGAAGAACTAGAAAAAGAAGCAAAAAAAGTTGAAGGATTTGATC

TGGTTCAGAAGCCAAGTTATTATGTTAGACTGGGATCCCTGTCTACCAAGCTTCACTC

CCGTGCCTACCAGCAGGCTCTCAGCAGGGTTAAAGAAGCTAAGCAAAAAAGCCAACAG

ACCATTTCTCAGCTCCATTCTACTGTTCACCTGATTGAATTTGCCAGGAAGAATGTGT

ATAGTGCCAATCAGAAAATTCAGGATGCTCAGGATAAGCTCTACCTCTCATGGGTAGA

GTGGAAAAGGAGCATTGGATATGATGATACTGATGAGTCCCACTGTGCTGAGCACATT

GAGTCACGTACTCTTGCAATTGCCCGCAACCTGACTCAGCAGCTCCAGACCACGTGCC

ACACCCTCCTGTCCAACATCCTTTGTGTACCACAGAACATCCCCCATCATTTTTTGCA

AAAGGGGGTGATGGCAGGCGACATCTACTCAGTGTTCCGGAATGCTGCCTCCTTTAAA

GAAGTGTCTGACAGCCTCCTCACTTCTAGCAAGGGGCAGCTGCAGAAAATGAAGGAAT

CTTTAGATGACGTGATGGATTATCTTGTTTACAAAACGCCCCTAAACTGGCTGGTAGG

TCCCTTTTATCCTCAGCTGACTGAGTCTCAGAATGCTCAGGACCAAGGTGCAGAGATG

GACAAGAGCAGCCAGGAGACCCAGCGATCTGAGCATAAAACTCATTAAACCTGCCCCT

ATCACTAGTGCATGCTGTGGCCAGACAGATGACACCTTTTGTTATGTTGAAATTAACT

TGCTAGGCAACCCTAAATTGGGAAGCAAGTAGCTAGTATAAAGGCCCTCAATTGTAGT

TGTTTCCAGCTGAATTAAGAGCTTTAAAGTTTCTGGCATTAGCAGATGATTTCTGTTC

ACCTGGTAAGAAAAGAATGATAGGCTTGTCAGAGCCTATAGCCA

ORF Start: ATG at 69 ORF Stop: TAA at 1380 SEQ ID NO: 1 S2 437 as MW at 48148.21cD
NOV3Sa, MASVAVDPQPSVVTRVVNLPLVSSTYDLMSSAYLSTKDQYPYLKSVCEMXENGVKTIT

PrOteln Sequence DAVTTTVTGAKDSVASTITGVMDKTKGAVTGSVEKTKSVVSGSINTVLGSRMMQLVSS

GVENALTKSELLVEQYLPLTEEELEKEAKKVEGFDLVQKPSYYVRLGSLSTKLHSRAY

QQALSRVKEAKQKSQQTISQLHSTVHLIEFARKNVYSANQKIQDAQDKLYLSWVEWKR

SIGYDDTDESHCAEHIESRTLAIARNLTQQLQTTCHTLLSNILCVPQNIPHHFLQKGV

MAGDIYSVFRNAASFKEVSDSLLTSSKGQLQKMKESLDDVMDYLVYKTPLNWLVGPFY

PQLTESQNAQDQGAEMDKSSQETQRSEHKTH

Further analysis of the NOV3Sa protein yielded the following properties shown in Table 3SB.
Table 35B. Protein Sequence Properties NOV35a PSort 0.6500 probability located in cytoplasm; 0.1000 probability located in analysis: mitochondrial matrix space; 0.1000 probability located in lysosome (lumen);
0.0000 probability located in endoplasmic reticulum (membrane) SignalP ~ No Known Signal Sequence Predicted analysis:
A search of the NOV35a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 35C.
Table 35C. Geneseq Results for NOV35a NOV35a Identities/

Geneseq Protein/Organism/Length Residues/SimilaritiesExpect [Patent #, for IdentifierDate] Match the Matched Value ResiduesRegion AAY99534 Human adipocyte-specific 1..300 289/300 (96%)e-161 differentiation-related 138..437289/300 (96%) protein ADRP -Homo Sapiens, 437 aa.

[W0200031532-A1, 02-JUN-2000]

AAW53264 Human adipocyte-specific 1..300 289/300 (96%)e-161 differentiation-related 138..437289/300 (96%) protein - Homo sapiens, 437 aa. [US5739009-A, APR-1998]

AAB58800 Breast and ovarian cancer51..300 238/250 (95%)e-133 associated antigen protein sequence 1..250 238/250 (95%) - Homo Sapiens, 250 aa.

[W0200055173-A1, 21-SEP-2000]

AAW06798 Murine p154 - Mus sp, 1..298 231/298 (77%)e-125 425 aa.

[US5541068-A, 30-JUL-1996]138..423256/298 (85%) AAR45151 Sequence of mouse adipocyte1..298 231/298 (77%)e-125 polypeptide (ap) p154 138..423256/298 (85%) - Acomys cahirinus, 425 aa. [US5268295-A, DEC-1993]

In a B LAST search of public sequence databases, the NOV35a protein was found to have homology to the proteins shown in the BLASTP data in Table 35D.
Table 35D. Public BLASTP Results for NOV35a NOV35a Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched Value Number Residues Portion CAC09025 SEQUENCE 22 FROM PATENT 1..300 289/300 (96%)e-160 W00031532 - Homo Sapiens138..437 289/300 (96%) (Human), 437 aa.

Q9BSC3 e-160 RELATED PROTEIN - Homo 138..437 289/300 (96%) sapiens (Human), 437 aa.

Q99541 Adipophilin (Adipose 1..300 287/300 (9S%)e-1 differentiation-related 138..437 287/300 (9S%) protein) (ADRP) - Homo Sapiens (Human), 437 aa.

Q9TUM6 Adipophilin (Adipose 1..282 239/282 (84%)e-132 differentiation-related 138..419 258/282 (90%) protein) (ADRP) - Bos taurus (Bovine), aa.

Q9MZES ADIPOSE DIFFERENTIATION-1..267 231/267 (86%)e-127 RELATED PROTEIN - Sus 138..404 ; 246/267 scrofa (91%) (Pig), 404 as (fragment).

PFam analysis predicts that the NOV3Sa protein contains the domains shown in the Table 35E.

Table 35E. Domain Analysis of NOV35a Identities/
Pfam Domain NOV35a Match Region Similarities Expect Value for the Matched Region SPX: domain 1 of 1 29..153 24/347 (7%) 8 80/347 (23%) perilipin: domain 1 of 1 1..259 166/411 (40%) 7.4e-89 247/411 (60%) EXAMPLE 36.
The NOV36 clone was analyzed, and the nucleotide and predicted polypeptide S sequences are shown in Table 36A.
Table36A. NOV36 Sequence Analysis SEQ ID NO: 153 35S by NOV36a, ACCTCTTTGCCACCAATACCATGAAGCTCTGCGTGACTGTCCTGTCTCTCCTCGTGCT

GCCTGCTGCTTTTCTTACACCGCGAGGAAGCTTCCTCACAACTTTGTGGTAGATTACT
SequeriCe ATGAGACCAGCAGCCTCTGCTCCCAGCCAGCTGTGGTATTCCAAACCAAAAGAGGCAA
GCAAGTCTGCGCTGACCCCAGTGAGTCCTGGGTCCAGGAGTACGTGTATGACCTGGAA
CTGAACTGAGCTGCTCAGAGACAGGACAGTCACGCAGAGCTTCATGGTATTGGTGGCA
AAGAGGT
ORF Start: ATG at 21 ORF Stop: TGA at 297 SEQ ID NO: 1 S4 92 as MW at 10146.61cD
NOV36a, MKLCVTVLSLLVLVAAFCSLALSAPMGSDPPTACCFSYTARKLPHNFVVDYYETSSLC
CGS8SO8-O1 PIOteln SQPAWFQTKRGKQVCADPSESWVQEYVYDLELN
Sequence SEQ ID NO: 15S 35S by NOV36b, A_CCTCTTTGCCACCAATACCATGAAGCTCTGCGTGACTGTCCTGTCTCTGAGCAGCTC

DNA

GACTTGCTTGCCTCTTTTGGTTTGGAATACCACAGCCGGCTGGGAGCAGAGGCTGCTG
SequeriCe GTCTCATAGTAATCTACCACAAAGTTGCGAGGAAGCTTCCTCGCGGTGTAAGAAAAGC

AGCAGGCGGTGGGAGGGTCTGAGCCCATTGGTGCTGAGAGTGCTAGAGAGCAGAAGGC

AGCTACTAGCACGAGGAGAGACAGGACAGTCACGCAGAGCTTCATGGTATTGGTGGCA

AAGAGGT

ORF Start: ATG at 21 ORF Stop: TAG
at 297 SEQ ID NO: 156 92 as MW at 10149.6kD

NOV36b, MKLCVTVLSLLVLVAAFCSPALSAPMGSDPPTACCFSYTARKLPRNFVVDYYETSSLC

PrOtelri Sequence SEQ ID NO: 157 219 by NOV36C, GGATCCGCACCAATGGGCTCAGACCCTCCCACCGCCTGCTGCTTTTCTTACACCGCGA

GCCAGCTGTGGTATTCCAAACCAAAAGAGGCAAGCAAGTCTGCGCTGACCCCAGTGAG
SequeriCe TCCTGGGTCCAGGAGTACGTGTATGACCTGGAACTGAACCTCGAG

ORF Start: GGA at 1 ORF Stop:

SEQ ID NO: 158 73 as MW at 817S.1kD

NOV36C, GSAPMGSDPPTACCFSYTARKLPRNFWDYYETSSLCSQPAWFQTKRGKQVCADPSE

170072532 PrOtelnS~QEYVYDLELNLE

Sequence SEQ ID NO: 159 219 by NOV36C1, GGATCCGCACCAATGGGCTCAGACCCTCCCACCGCCTGCTGCTTTTCTTACACCGCGA

GCCAGCTGTGGTATTCCAAACCAAAAGAAGCAAGCAAGTCTGTGCTGATCCCAGTGAA
SequeriCe TCCTGGGTCCAGGAGTACGTGTATGACCTGGAACTGAACCTCGAG

ORF Start: GGA at 1 ORF Stop:

SEQ ID NO: 160 73 as MW at 8205.1kD

NOV36(1, GSAPMGSDPPTACCFSYTARKLPRNFWDYYETSSLCSQPAWFQTKRSKQVCADPSE

170072551 PrOtelriS~QEYVYDLELNLE

Sequence SEQ ID NO: 161 219 by NOV36e, GGATCCGCACCAATGGGCTCAGACCCTCCCACCGCTTGCTGCTTTTCTTACACCGCGA

GCCAGCTGTGGTATTCCAAACCAAAAGAAGCAAGCAAGTCTGTGCTGATCCCAGTGAA
Sequence TCCTGGGTCCAGGAGTACGTGTATGACCTGGAACTGAACCTCGAG

ORF Start: GGA at 1 ORF Stop:

SEQ ID NO: 162 73 MW at 8205.1kD
as NOV36e, GSAPMGSDPPTACCFSYTARKLPRNFWDYYETSSLCSQPAWFQTKRSKQVCADPSE

170072$55 PrOtelriSWVQEYVYDLELNLE

Sequence SEQ ID NO: 163 301 by NOV36f, CAGCCTCACCTCTGAGAAAACCTCTTTTCCACCAATACCATGAAGCTCTGCGTGACTG

DNA

TGGTATTCCAAACCAAAAGAAGCAAGCAAGTCTGTGCTGATCCCAGTGAATCCTGGGT
SequeriCe CCAGGAGTACGTGTATGACCTGGAACTGAACTGAGCTGCTCAGAGACAGGAAGTCTTC

AGGGAAGGTCACCTGAGCCCGGATGCTTCTCCATGAGACACATCTCCTCCATACTCAG
GACTCCTCTCA
ORF Start: ATG at 40 ORF Stop: TGA at 154 SEQ ID NO: 164 38 as MW at 3940.8kD
NOV36f, MKLCVTVLSLLMLVAAFCSPALSASCGIPNQKKQASLC
CG58508-03 Protein Sequence Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 36B.
Table 36B. Comparison of NOV36a against NOV36b through NOV36f.
NOV36a Residues/Identities/

Protein SequenceMatch ResiduesSimilarities for the Matched Region NOV36b 15..92 76/78 (97%) 15..92 76/78 (97%) NOV36c 23..92 69/70 (98%) 2..71 69/70 (98%) NOV36d 23..92 68/70 (97%) 2..71 68/70 (97%) NOV36e 23..92 68/70 (97%) 2..71 68/70 (97%) NOV36f 1..27 23/27 (85%) 1..27 24/27 (88%) Further analysis of the NOV36a protein yielded the following properties shown in Table 36C.
Table 36C. Protein Sequence Properties NOV36a PSort 0.8200 probability located in outside; 0.1000 probability located in endoplasmic analysis: reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in lysosome (lumen) SignalP Likely cleavage site between residues 24 and 25 analysis:
A search of the NOV36a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 36D.
Table 36D. Geneseq Results for NOV36a Geneseq Protein/Organism/Length [Patent #, NOV36a Identities/ ERpect Identifier Date] Residues/ Similarities Value ResiduesMatched Region AAR36770 MIP-lbeta - Homo Sapiens, 1..92 89/92 (96%)9e-48 92 aa.

[W09309799-A, 27-MAY-1993]1..92 90/92 (97%) AAB15789 Human chemokine MIPlbeta 1..92 88/92 (95%)6e-47 SEQ ID

NO: 20 - Homo Sapiens, 1..92 89/92 (96%) 92 aa.

[W0200042071-A2, 20-JUL-2000]

AAW82717 Human Act-2 protein - Homo1..92 88/92 (95%)6e-47 Sapiens, 92 aa. [W09854326-A1, 03-DEC-1..92 89/92 (96%) 1998]

AAW76225 Human chemokine MIP-lbeta 1..92 88/92 (95%)6e-47 domain protein fragment - Homo 1..92 89/92 (96%) Sapiens, 92 aa. [W09838212-A2, 03-SEP-1998]

AAW76223 Human chemokine MIP-lbeta 1..92 88/92 (95%)6e-47 domain protein from clone MPB-X 1..92 89/92 (96%) - Homo sapiens, 331 aa. [W09838212-A2, SEP-1998]

In a BLAST search of public sequence databases, the NOV36a protein was found to have homology to the proteins shown in the BLASTP data in Table 36E.
Table 36E. Public BLASTP Results for NOV36a NOV36a Identities/

Protein Similarities Residues/ Expect AccessionProtein/Organism/Length Match for the Value Number ResiduesMatched Portion P13236 Small inducible cytokine A4 1..92 88/92 2e-46 precursor (95%) (Macrophage inflammatory protein1..92 89/92 1-beta) (96%) (MIP-1-beta) (T-cell activation protein 2) (ACT-2) (PAT 744) (H400) (SIS-gamma) (Lymphocyte activation gene-1 protein) (LAG-1 ) (HC21 ) (G-26 T lymphocyte-secreted protein) - Homo Sapiens (Human), 92 aa.

P46632 Small inducible cytokine A4 1..92 75/92 7e-39 precursor (81%) (Macrophage inflammatory protein1..92 84/92 1-beta) (90%) (MIP-1-beta) (Immune activation protein 2) (ACT-2) - Oryctolagus cuniculus (Rabbit), 92 aa.

P50230 Small inducible cytokine A4 1..92 71/92 3e-38 precursor (77%) (Macrophage inflammatory protein1..92 81/92 1-beta) (87%) (MIP-1-beta) - Rattus norvegicus (Rat), 92 aa.

P14097 Small inducible cytokine A4 1..92 69/92 1e-36 precursor (75%) ~

(Macrophage inflammatory protein1..92 82/92 1-beta) (89%) (MIP-1-beta) (H400 protein) (SIS-gamma) (ACT2) - Mus musculus (Mouse), 92 aa.

CAA01323HUMAN ACT-2 SYNTHETIC GENE 19..92. 69/74 2e-35 (93%) PROTEIN - synthetic construct,1..74 69/74 74 as (93%) (fragment).

PFam analysis predicts that the NOV36a protein contains the domains shown in the Table 36F.
Table 36F. Domain Analysis of NOV36a Identities/
Pfam Domain NOV36a Match Region Similarities Expect Value for the Matched Region ILB: domain 1 of 1 24..89 25/70 (36%) 2.6e-32 60/70 (86%) EXAMPLE 37.
The NOV37 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 37A.
Table 37A. NOV37 Sequence Analysis SEQ ID NO: 165 ~ 5285 by NOV37a, ~GGCCGGGGGAGGGGGCCGGACCGCGCGCGACCGGTCGCGCCCGCTGGGGCCCGCGATG

CGCACGGCCGGCTGCGGAGGATCACCTACGTGGTGCACCCGGGCCCCGGCCTGGCAGC
SequeriCe CGGCGCCTTGCCCCTGAGCGGGCCCCCGCGTTCGCGGACATTCAACGTCGCGCTCAAC
GCCAGGTACAGCCGCAGCTCGGCGGCTGCCGGCGCCCCCAGCCGTGCCTCCCCCGGGG
TCCCCTCGGAGAGGACCCGGCGCACGAGCAAGCCGGGCGGCGCGGCCCTGCAGGGGCT
CAGACCGCCGCCGCCGCCGCCGCCGGAGCCTGCGCGTCCCGCGGTCCCCGGCGGGCAG
CTCCACCCCAATCCCGGCGGCCACCCGGCAGCCGCCCCGTTCACCAAACAAGGCAGGC
AAGTTGTGCGCTCCAAGGTGCCGCAGGAGACCCAGAGCGGCGGAGGCTCTAGGCTGCA
GGTTCACCAGAAGCAGCAGCTGCAGGGGGTCAATGTCTGTGGAGGGCGGTGCTGTCAT
GGCTGGAGTAAGGCCCCTGGCTCCCAGAGGTGCACCAAACCTAGCTGTGTTCCGCCAT
GTCAGAATGGAGGGATGTGTCTCCGGCCACAACTCTGTGTGTGTAAACCAGGGACCAA
GGGCAAAGCCTGTGAAACAATAGCTGCCCAGGACACCTCGTCACCAGTCTTTGGAGGG
CAGAGTCCTGGGGCTGCTTCCTCGTGGGGCCCTCCTGAGCAAGCAGCAAAGCATACTT
CATCTAAGAAGGCAGACACTCTACCAAGAGTCAGCCCTGTGGCCCAGATGACCTTAAC
CCTCAAGCCGAAGCCTTCAGTGGGACTCCCCCAGCAGATACATTCTCAAGTGACTCCT
CTTTCTTCCCAGAGCGTGGTTATTCACCATGGCCAGACCCAGGAATACGTGCTCAAGC
CCAAGTACTTTCCAGCCCAGAAGGGGATTTCAGGAGAACAGTCCACTGAAGGTTCTTT
CCCTTTAAGATATGTGCAGGATCAAGTTGCGGCACCTTTTCAGCTGAGTAACCACACT
.TCTGT
GCTGTCAGAACAGCTGTGAGAAGGGGAACACCACCACTCTCATTAGTGAGAATGGTCA
TGCTGCCGACACCCTGACGGCCACGAACTTCCGAGTGGTAATTTGCCATCTTCCATGT
ATGAATGGTGGCCAGTGCAGTTCAAGGGACAAATGTCAGTGCCCTCCAAATTTCACAG
GAAAACTTTGTCAGATCCCAGTCCATGGTGCCAGCGTGCCTAAACTTTATCAGCATTC
CCAGCAGCCAGGCAAGGCGTTGGGGACGCATGTCATCCATTCAACACATACCTTGCCT
CTGACCGTGACTAGCCAGCAAGGAGTCAAAGTGAAATTTCCTCCTAACATAGTCAATA
TCCATGTGAAACATCCTCCTGAAGCTTCCGTCCAGATACATCAGGTTTCAAGAATTGA

TGGCCCAACAGGCCAGAAGACAAAAGAAGCTCAACCAGGCCAATCCCAAGTCTCGTAC
CAAGGGCTTCCTGTCCAGAAGACCCAGACCATACATTCCACATACTCCCACCAGCAGG
TCATTCCTCACGTCTACCCCGTGGCTGCTAAGACACAGCTTGGCCGGTGCTTCCAGGA
AACCATTGGGTCACAGTGTGGCAAAGCGCTCCCTGGCCTTTCAAAGCAAGAGGACTGC
TGTGGAACTGTGGGTACCTCCTGGGGCTTTAACAAATGCCAGAAATGCCCCAAGAAAC
CATCTTATCATGGATACAACCAAATGATGGAATGCCTACCGGGTTATAAGCGGGTTAA
CAACACCTTTTGCCAAGATATTAATGAATGTCAGCTACAAGGTGTATGCCCTAATGGT
GAGTGTTTGAATACCATGGGCAGCTATCGATGTACCTGCAAAATAGGATTTGGGCCGG
ATCCTACCTTTTCAAGTTGTGTTCCTGATCCCCCTGTGATCTCGGAAGAGAAAGGGCC
CTGTTACCGACTTGTCAGTTCTGGAAGACAGTGTATGTACCCTCTGTCTGTTCACCTC
ACCAAGCAGCTCTGCTGTTGTAGTGTGGGCAAGGCCTGGGGCCCACACTGTGAGAAAT
GTCCCCTTCCAGGCACAGCTGCTTTTAAGGAAATCTGTCCTGGTGGAATGGGTTATAC
GGTTTCTGGCGTTCATAGACGCAGGCCAATCCATCACCATGTAGGTAAAGGACCTGTA
TTTGTCAAGCCAAAGAACACTCAACCTGTTGCTAAAAGTACTCATCCTCCACCTCTCC
CAGCCAAGGAAGAGCCAGTGGAGGCCCTGACCTTCTCCCGGGAACACGGGCCAGGAGT
GGCGGAGCCAGAAGTGGCAACTGCACCCCCTGAAAAGGAAATACCTTCATTGGATCAA
GAGAAAACCAAACTTGAGCCTGGTCAACCCCAGCTGTCTCCAGGCATTTCCGCTATTC
ATCTGCATCCACAGTTTCCAGTAGTGATTGAAAAAACATCACCTCCTGTGCCTGTTGA
AGTAGCTCCTGAAGCTTCTACGTCTAGTGCCAGCCAAGTGATTGCTCCTACTCAAGTG
ACAGAAATCAATGAATGTACTGTGAACCCTGATATCTGTGGAGCAGGACACTGCATTA
ACCTACCAGTGAGATATACCTGTATATGCTACGAGGGCTACAGGTTCAGTGAACAACA
GAGGAAATGTGTGTATATTGATGAGTGTACTCAGGTCCAACACCTCTGCTCCCAGGGC
CGCTGTGAAAACACCGAGGGAAGTTTCTTGTGCATTTGCCCAGCAGGATTTATGGCCA
GTGAGGAGGGTACTAACTGCATAGATGTTGACGAATGCCTGAGGCCGGACGTCTGTGG
GGAGGGGCACTGTGTCAATACTGTGGGGGCCTTCCGGTGTGAATACTGTGACAGCGGG
TACCGCATGACTCAGAGAGGCCGTTGTGAGGATATTGATGAATGTTTGAATCCAAGCA
CTTGTCCAGATGAGCAGTGTGTGAATTCTCCTGGATCTTACCAGTGCGTTCCCTGCAC
AGAAGGATTCCGAGGCTGGAATGGACAGTGCCTTGATGTGGACGAGTGCCTGGAACCA
AACGTCTGCGCAAATGGTGATTGTTCCAACCTTGAAGGCTCCTACATGTGTTCATGCC
ACAAAGGCTATACCCGGACTCCGGACCACAAGCACTGTAGAGATATTGATGAATGTCA
GTGTAAACGGGCAGTGCAAAAATACCGAGGGCTCCTTCAGGTGC
GTACCAGCTGTCGGCAGCTAAAGACCAGTGTGAAGACATTGATG
CATCTCTGTGCTCATGGGCAGTGCAGGAACACTGAGGGCTCTTT
ACCAGGGTTACAGAGCATCTGGGCTTGGAGACCACTGTGAAGAT
GGAGGACAAGAGTGTTTGCCAGAGAGGAGACTGCATTAATACTG
CAGGGTCCTATGATTGTACTTGTCCGGATGGATTTCAGCTAGATGACAATAAAACATG
TCAAGATATTAATGAATGTGAACATCCAGGGCTCTGTGGTCCGCAAGGGGAGTGCCTA
TTGTGTCTGCCAGCAGGGTTTCTCAATCTCTGCAGATG
GCCGTACGTGTGAAGATATTGATGAATGTGTAAACAACACTGTTTGTGACAGTCACGG
GTTTTGTGACAATACAGCTGGCTCCTTCCGCTGCCTCTGTTATCAGGGCTTTCAAGCC
CCACAGGATGGGCAAGGGTGTGTGGATGTGAATGAATGTGAACTGCTCAGTGGGGTGT
GTGGTGAAGCCTTCTGTGAAAACGTGGAAGGGTCCTTCCTGTGCGTGTGTGCTGATGA
CCCATGACTGGGCAGTGCCGCTCCCGGACCTCCACAGATTTA
GATGTAGATGTAGATCAACCCAAAGAAGAAAAGAAAGAATGCTACTATAATCTCAATG
ACGCCAGTCTCTGTGATAATGTGTTGGCCCCCAATGTCACGAAACAAGAATGCTGCTG
TACATCAGGCGTGGGATGGGGAGATAACTGCGAAATCTTCCCCTGCCCGGTCTTGGGA
CATCTTCTGAAGCTGGTGGTGAGAACTATAAAGATGCAGATGAATGCCTACTTTTTGG
ACAAGAAATCTGCAAAAATGGTTTCTGTTTGAACACTCGGCCTGGGTATGAATGCTAC
TGTAAGCAAGGGACGTACTATGATCCTGTGAAACTGCAGTGCTTTGATATGGATGAAT
GTCAAGACCCCAGTAGTTGTATTGATGGCCAGTGTGTTAATACAGAGGGCTCTTACAA
CTGCTTCTGTACTCACCCCATGGTCCTGGATGCGTCAGAAAAAAGATGTATACGACCG
GCTGAGTCAAACGAACAAATAGAAGAAACTGATGTCTACCAAGATTTGTGCTGGGAAC
ATCTGAGTGATGAATACGTGTGTAGCCGGCCTCTTGTGGGCAAGCAGACAACGTACAC
TGAGTGCTGCTGTCTGTATGGAGAGGCCTGGGCGATGCAGTGTGCCCTCTGCCCCCTG
AAGGATTCAGATGACTATGCTCAGCTGTGTAACATCCCCGTGACGGGACGCCGGCAGC
CATATGGACGGGACGCCTTGGTTGACTTCAGTGAACAGTATACTCCAGAAGCCGATCC
CTACTTCATCCAAGACCGTTTTCTAAATAGCTTTGAGGAGTTACAGGCTGAGGAATGC
GGCATCCTCAATGGATGTGAAAATGGTCGCTGTGTGAGGGTCCAGGAAGGTTACACCT
GCGATTGCTTTGATGGGTATCACTTGGATACTGCCAAGATGACCTGTTTCGATGTAAA
TGAATGCGATGAGTTGAACAACCGGATGTCTCTCTGCAAGAATGCCAAGTGCATTAAC

ACCGATGGTTCCTACAAGTGTTTGTGTCTGCCAGGCTACGTGCCTTCTGACAAGCCAA

ACTACTGCACTCCGTTGAATACCGCCTTGAATTTAGAGAAAGACAGTGACCTGGAGTG

AAACAGAATCTACATAACCTAAGCCCATATACTCTGCACTGTGTAAAGGAAAAGGGAG

AAATGTA

ORF Start: ATG ORF Stop:
at S6 TGA at SEQ ID NO: 166 1721 as MW at 186900.6kD

NOV37a, MAGAWLRWGLLLWAGLLASSAHGRLRRITYWHPGPGLAAGALPLSGPPRSRTFNVAL

CGS9819-O1 N~YSRSSAAAGAPSRASPGVPSERTRRTSKPGGAALQGLRPPPPPPPEPARPAVPGG

PrOtelri QLHPNPGGHPAAAPFTKQGRQWRSKVPQETQSGGGSRLQVHQKQQLQGVNVCGGRCC

Se uence HGWSKAPGSQRCTKPSCVPPCQNGGMCLRPQLCVCKPGTKGKACETIAAQDTSSPVFG

GQSPGAASSWGPPEQAAKHTSSKKADTLPRVSPVAQMTLTLKPKPSVGLPQQIHSQVT

PLSSQSWIHHGQTQEYVLKPKYFPAQKGISGEQSTEGSFPLRYVQDQVAAPFQLSNH

TGRIKWFTPSICKVTCTKGSCQNSCEKGNTTTLISENGHAADTLTATNFRWICHLP

CMNGGQCSSRDKCQCPPNFTGKLCQIPVHGASVPKLYQHSQQPGKALGTHVIHSTHTL

PLTVTSQQGVKVKFPPNIVNIHVKHPPEASVQIHQVSRIDGPTGQKTKEAQPGQSQVS

YQGLPVQKTQTIHSTYSHQQVIPHWPVAAKTQLGRCFQETIGSQCGKALPGLSKQED

CCGTVGTSWGFNKCQKCPKKPSYHGYNQMMECLPGYKRVNNTFCQDINECQLQGVCPN

GECLNTMGSYRCTCKIGFGPDPTFSSCVPDPPVISEEKGPCYRLVSSGRQCMYPLSVH

LTKQLCCCSVGKAWGPHCEKCPLPGTAAFKEICPGGMGYTVSGVHRRRPIHHHVGKGP

VFVKPKNTQPVAKSTHPPPLPAKEEPVEALTFSREHGPGVAEPEVATAPPEKEIPSLD

QEKTKLEPGQPQLSPGISAIHLHPQFPWIEKTSPPVPVEVAPEASTSSASQVIAPTQ

VTEINECTVNPDICGAGHCINLPVRYTCICYEGYRFSEQQRKCWIDECTQVQHLCSQ

GRCENTEGSFLCICPAGFMASEEGTNCIDVDECLRPDVCGEGHCVNTVGAFRCEYCDS

GYRMTQRGRCEDIDECLNPSTCPDEQCVNSPGSYQCVPCTEGFRGWNGQCLDVDECLE

PNVCANGDCSNLEGSYMCSCHKGYTRTPDHKHCRDIDECQQGNLCVNGQCKNTEGSFR

CTCGQGYQLSAAKDQCEDIDECQHRHLCAHGQCRNTEGSFQCVCDQGYRASGLGDHCE

DINECLEDKSVCQRGDCINTAGSYDCTCPDGFQLDDNKTCQDINECEHPGLCGPQGEC

LNTEGSFHCVCQQGFSISADGRTCEDIDECVNNTVCDSHGFCDNTAGSFRCLCYQGFQ

APQDGQGCVDVNECELLSGVCGEAFCENVEGSFLCVCADENQEYSPMTGQCRSRTSTD

LDVDVDQPKEEKKECYYNLNDASLCDNVLAPNVTKQECCCTSGVGWGDNCEIFPCPVL

GTAEFTEMCPKGKGFVPAGESSSEAGGENYKDADECLLFGQEICKNGFCLNTRPGYEC

YCKQGTYYDPVKLQCFDMDECQDPSSCIDGQCVNTEGSYNCFCTHPMVLDASEKRCIR

PAESNEQIEETDWQDLCWEHLSDEYVCSRPLVGKQTTYTECCCLYGEAWAMQCALCP

LKDSDDYAQLCNIPVTGRRQPYGRDALVDFSEQYTPEADPYFIQDRFLNSFEELQAEE

CGILNGCENGRCVRVQEGYTCDCFDGYHLDTAKMTCFDVNECDELNNRMSLCKNAKCI

NTDGSYKCLCLPGYVPSDKPNYCTPLNTALNLEKDSDLE

SEQ ID NO: 167 5126 by NOV37b, GGCCGGGGGAGGGGGCCGGACCGCGCGCGACCGGTCGCGCCCGCTGGGGCCCGCGATG

DNA

CGCACGGCCGGCTGCGGAGGATCACCTACGTGGTGCACCCGGGCCCCGGCCTGGCAGC
SeC1t12riCe CGGCGCCTTGCCCCTGAGCGGGCCCCCGCGTTCGCGGACATTCAACGTCGCGCTCAAC

GCCAGGTACAGCCGCAGCTCGGCGGCTGCCGGCGCCCCCAGCCGTGCCTCCCCCGGGG

TCCCCTCGGAGAGGACCCGGCGCACGAGCAAGCCGGGCGGCGCGGCCCTGCAGGGGCT

CAGACCGCCGCCGCCGCCGCCGCCGGAGCCTGCGCGTCCCGCGGTCCCCGGCGGGCAG

CTCCACCCCAATCCCGGCGGCCACCCGGCAGCCGCCCCGTTCACCAAACAAGGCAGGC

AAGTTGTGCGCTCCAAGGTGCCGCAGGAGACCCAGAGCGGCGGAGGCTCTAGGCTGCA

GGTTCACCAGAAGCAGCAGCTGCAGGGGGTCAATGTCTGTGGAGGGCGGTGCTGTCAT

GGCTGGAGTAAGGCCCCTGGCTCCCAGAGGTGCACCAAACCTAGCTGTGTTCCGCCAT

GTCAGAATGGAGGGATGTGTCTCCGGCCACAACTCTGTGTGTGTAAACCAGGGACCAA

GGGCAAAGCCTGTGAAACAATAGCTGCCCAGGACACCTCGTCACCAGTCTTTGGAGGG

CAGAGTCCTGGGGCTGCTTCCTCGTGGGGCCCTCCTGAGCAAGCAGCAAAGCATACTT

CATCTAAGAAGGCAGACACTCTACCAAGAGTCAGCCCTGTGGCCCAGATGACCTTAAC

CCTCAAGCCGAAGCCTTCAGTGGGACTCCCCCAGCAGATACATTCTCAAGTGACTCCT

CTTTCTTCCCAGAGCGTGGTTATTCACCATGGCCAGACCCAGGAATACGTGCTCAAGC

CCAAGTACTTTCCAGCCCAGAAGGGGATTTCAGGAGAACAGTCCACTGAAGGTTCTTT

CCCTTTAAGATATGTGCAGGATCAAGTTGCGGCACCTTTTCAGCTGAGTAACCACACT

GGCCGCATCAAGGTGGTCTTTACTCCGAGCATCTGTAAAGTGACCTGCACCAAGGGCA

GCTGTCAGAACAGCTGTGAGAAGGGGAACACCACCACTCTCATTAGTGAGAATGGTCA

TGCTGCCGACACCCTGACGGCCACGAACTTCCGAGTGGTAATTTGCCATCTTCCATGT
ATGAATGGTGGCCAGTGCAGTTCAAGGGACAAATGTCAGTGCCCTCCAAATTTCACAG
GAAAACTTTGTCAGATCCCAGTCCATGGTGCCAGCGTGCCTAAACTTTATCAGCATTC
CCAGCAGCCAGGCAAGGCGTTGGGGACGCATGTCATCCATTCAACACATACCTTGCCT
CTGACCGTGACTAGCCAGCAAGGAGTCAAAGTGAAATTTCCTCCTAACATAGTCAATA
TCCATGTGAAACATCCTCCTGAAGCTTCCGTCCAGATACATCAGGTTTCAAGAATTGA
TGGCCCAACAGGCCAGAAGACAAAAGAAGCTCAACCAGGCCAATCCCAAGTCTCGTAC
CAAGGGCTTCCTGTCCAGAAGACCCAGACCATACATTCCACATACTCCCACCAGCAGG
TCATTCCTCACGTCTACCCCGTGGCTGCTAAGACACAGCTTGGCCGGTGCTTCCAGGA
TGTGGAACTGTGGGTACCTCCTGGGGCTTTAACAAATGCCAGAAATGCCCCAAGAAAC
CATCTTATCATGGATACAACCAAATGATGGAATGCCTACCGGGTTATAAGCGGGTTAA
CAACACCTTTTGCCAAGATATTAATGAATGTCAGCTACAAGGTGTATGCCCTAATGGT
GAGTGTTTGAATACCATGGGCAGCTATCGATGTACCTGCAAAATAGGATTTGGGCCGG
ATCCTACCTTTTCAAGTTGTGTTCCTGATCCCCCTGTGATCTCGGAAGAGAAAGGGCC
CTGTTACCGACTTGTCAGTTCTGGAAGACAGTGTATGCACCCTCTGTCTGTTCACCTC
ACCAAGCAGCTCTGCTGTTGTAGTGTGGGCAAGGCCTGGGGCCCACACTGTGAGAAAT
GTCCCCTTCCAGGCACAGCCAAGGAAGAGCCAGTGGAGGCCCTGACCTTCTCCCGGGA
CCTTCATTGGATCAAGAGAAAACCAAACTTGAGCCTGGTCAACCCCAGCTGTCTCCAG
GCATTTCCGCTATTCATCTGCATCCACAGTTTCCAGTAGTGATTGAAAAAACATCACC
TCCTGTGCCTGTTGAAGTAGCTCCTGAAGCTTCTACGTCTAGTGCCAGCCAAGTGATT
GCTCCTACTCAAGTGACAGAAATCAATGAATGTACTGTGAACCCTGATATCTGTGGAG
CAGGACACTGCATTAACCTACCAGTGAGATATACCTGTATATGCTACGAGGGCTACAG
GTTCAGTGAACAACAGAGGAAATGTGTGTATATTGATGAGTGTACTCAGGTCCAACAC
CTCTGCTCCCAGGGCCGCTGTGAAAACACCGAGGGAAGTTTCTTGTGCATTTGCCCAG
CAGGATTTATGGCCAGTGAGGAGGGTACTAACTGCATAGATGTTGACGAATGCCTGAG
GCCGGACGTCTGTGGGGAGGGGCACTGTGTCAATACTGTGGGGGCCTTCCGGTGTGAA
TACTGTGACAGCGGGTACCGCATGACTCAGAGAGGCCGTTGTGAGGATATTGATGAAT
GTTTGAATCCAAGCACTTGTCCAGATGAGCAGTGTGTGAATTCTCCTGGATCTTACCA
GTGCGTTCCCTGCACAGAAGGATTCCGAGGCTGGAATGGACAGTGCCTTGATGTGGAC
GAGTGCCTGGAACCAAACGTCTGCGCAAATGGTGATTGTTCCAACCTTGAAGGCTCCT
ACATGTGTTCATGCCACAAAGGCTATACCCGGACTCCGGACCACAAGCACTGTAGAGA
TATTGATGAATGTCAGCAAGGGAATCTATGTGTAAACGGGCAGTGCAAAAATACCGAG
GGCTCCTTCAGGTGCACCTGTGGACAGGGGTACCAGCTGTCGGCAGCTAAAGACCAGT
GTGAAGACATTGATGAATGCCAGCACCGTCATCTCTGTGCTCATGGGCAGTGCAGGAA
CACTGAGGGCTCTTTTCAATGTGTGTGTGACCAGGGTTACAGAGCATCTGGGCTTGGA
GACCACTGTGAAGATATCAATGAATGCTTGGAGGACAAGAGTGTTTGCCAGAGAGGAG
ACTGCATTAATACTGCAGGGTCCTATGATTGTACTTGTCCGGATGGATTTCAGCTAGA
TGACAATAAAACATGTCAAGATATTAATGAATGTGAACATCCAGGGCTCTGTGGTCCG
CAAGGGGAGTGCCTAAACACAGAGGGTTCTTTCCATTGTGTCTGCCAGCAGGGTTTCT
CAATCTCTGCAGATGGCCGTACGTGTGAAGATATTGATGAATGTGTAAACAACACTGT
TTGTGACAGTCACGGGTTTTGTGACAATACAGCTGGCTCCTTCCGCTGCCTCTGTTAT
CAGGGCTTTCAAGCCCCACAGGATGGGCAAGGGTGTGTGGATGTGAATGAATGTGAAC
TGCTCAGTGGGGTGTGTGGTGAAGCCTTCTGTGAAAACGTGGAAGGGTCCTTCCTGTG
CGTGTGTGCTGATGAAAACCAAGAGTACAGCCCCATGACTGGGCAGTGCCGCTCCCGG
ACCTCCACAGATTTAGATGTAGATGTAGATCAACCCAAAGAAGAAAAGAAAGAATGCT
ACTATAATCTCAATGACGCCAGTCTCTGTGATAATGTGTTGGCCCCCAATGTCACGAA
ACAAGAATGCTGCTGTACATCAGGCGTGGGATGGGGAGATAACTGCGAAATCTTCCCC
TGTGTCCCAAAGGGAAAGGTTTTG
TGCTGGAGAATCATCTTCTGAAGCTGGTGGTGAGAACTATAAAGATGCAGATGA
CTACTTTTTGGACAAGAAATCTGCAAAAATGGTTTCTGTTTGAACACTCGGCCT
ATGAATGCTACTGTAAGCAAGGGACGTACTATGATCCTGTGAAACTGCAGTGCT
TATGGATGAATGTCAAGACCCCAGTAGTTGTATTGATGGCCAGTGTGTTAATAC
GGCTCTTACAACTGCTTCTGTACTCACCCCATGGTCCTGGATGCGTCAGAAAAA
GTATACGACCGGCTGAGTCAAACGAACAAATAGAAGAAACTGATGTCTACCAAG
ATTTGTGCTGGGAACATCTGAGTGATGAATACGTGTGTAGCCGGCCTCTTGTGGGCAA
GCAGACAACGTACACTGAGTGCTGCTGTCTGTATGGAGAGGCCTGGGCGATGCAGTGT
GCCCTCTGCCCCCTGAAGGATTCAGATGACTATGCTCAGCTGTGTAACATCCCCGTGA
CGGGACGCCGGCAGCCATATGGACGGGACGCCTTGGTTGACTTCAGTGAACAGTATAC
TCCAGAAGCCGATCCCTACTTCATCCAAGACCGTTTTCTAAATAGCTTTGAGGAGTTA

CAGGCTGAGGAATGCGGCATCCTCAATGGATGTGAAAATGGTCGCTGTGTGAGGGTCC

AGGAAGGTTACACCTGCGATTGCTTTGATGGGTATCACTTGGATACTGCCAAGATGAC

CTGTTTCGATGTAAATGAATGCGATGAGTTGAACAACCGGATGTCTCTCTGCAAGAAT

GCCAAGTGCATTAACACCGATGGTTCCTACAAGTGTTTGTGTCTGCCAGGCTACGTGC

CTTCTGACAAGCCAAACTACTGCACTCCGTTGAATACCGCCTTGAATTTAGAGAAAGA

CAGTGACCTGGAGTGAAACAGAATCTACATAACCTAAGCCCATATACTCTGCACTGTG

TAAAGGAAAAGGGAGAAATGTA

ORF Start: ATG ORF Stop:
at S6 TGA at SEQ ID NO: 168 1668 as MW at 181174.9kD

NOV37b, MAGAWLRWGLLLWAGLLASSAHGRLRRITYVVHPGPGLAAGALPLSGPPRSRTFNVAL

CGS9819-O2 N'~YSRSSAAAGAPSRASPGVPSERTRRTSKPGGAALQGLRPPPPPPPEPARPAVPGG

PTOtelri QLHPNPGGHPAAAPFTKQGRQVVRSKVPQETQSGGGSRLQVHQKQQLQGVNVCGGRCC

Se uence HGWSKAPGSQRCTKPSCVPPCQNGGMCLRPQLCVCKPGTKGKACETIAAQDTSSPVFG

GQSPGAASSWGPPEQAAKHTSSKKADTLPRVSPVAQMTLTLKPKPSVGLPQQIHSQVT

PLSSQSWIHHGQTQEYVLKPKYFPAQKGISGEQSTEGSFPLRYVQDQVAAPFQLSNH

TGRIKWFTPSICKVTCTKGSCQNSCEKGNTTTLISENGHAADTLTATNFRWICHLP

CMNGGQCSSRDKCQCPPNFTGKLCQIPVHGASVPKLYQHSQQPGKALGTHVIHSTHTL

PLTVTSQQGVKVKFPPNIVNIHVKHPPEASVQIHQVSRIDGPTGQKTKEAQPGQSQVS

YQGLPVQKTQTIHSTYSHQQVIPHVYPVAAKTQLGRCFQETIGSQCGKALPGLSKQED

CCGTVGTSWGFNKCQKCPKKPSYHGYNQMMECLPGYKRVNNTFCQDINECQLQGVCPN

GECLNTMGSYRCTCKIGFGPDPTFSSCVPDPPVISEEKGPCYRLVSSGRQCMHPLSVH

LTKQLCCCSVGKAWGPHCEKCPLPGTAKEEPVEALTFSREHGPGVAEPEVATAPPEKE

IPSLDQEKTKLEPGQPQLSPGISAIHLHPQFPWIEKTSPPVPVEVAPEASTSSASQV

IAPTQVTEINECTVNPDICGAGHCINLPVRYTCICYEGYRFSEQQRKCVYIDECTQVQ

HLCSQGRCENTEGSFLCICPAGFMASEEGTNCIDVDECLRPDVCGEGHCVNTVGAFRC

EYCDSGYRMTQRGRCEDIDECLNPSTCPDEQCVNSPGSYQCVPCTEGFRGWNGQCLDV

DECLEPNVCANGDCSNLEGSYMCSCHKGYTRTPDHKHCRDIDECQQGNLCVNGQCKNT

EGSFRCTCGQGYQLSAAKDQCEDIDECQHRHLCAHGQCRNTEGSFQCVCDQGYRASGL

GDHCEDINECLEDKSVCQRGDCINTAGSYDCTCPDGFQLDDNKTCQDINECEHPGLCG

PQGECLNTEGSFHCVCQQGFSISADGRTCEDIDECVNNTVCDSHGFCDNTAGSFRCLC

YQGFQAPQDGQGCVDVNECELLSGVCGEAFCENVEGSFLCVCADENQEYSPMTGQCRS

RTSTDLDVDVDQPKEEKKECYYNLNDASLCDNVLAPNVTKQECCCTSGVGWGDNCEIF

PCPVLGTAEFTEMCPKGKGFVPAGESSSEAGGENYKDADECLLFGQEICKNGFCLNTR

PGYECYCKQGTYYDPVKLQCFDMDECQDPSSCIDGQCVNTEGSYNCFCTHPMVLDASE

KRCIRPAESNEQIEETDVYQDLCWEHLSDEYVCSRPLVGKQTTYTECCCLYGEAWAMQ

CALCPLKDSDDYAQLCNIPVTGRRQPYGRDALVDFSEQYTPEADPYFIQDRFLNSFEE

LQAEECGILNGCENGRCVRVQEGYTCDCFDGYHLDTAKMTCFDVNECDELNNRMSLCK

NAKCINTDGSYKCLCLPGYVPSDKPNYCTPLNTALNLEKDSDLE

SEQ ID NO: 169 6074 by NOV37C, GGCCGGGGGAGGGGGCCGGACCGCGCGCGACCGGTCGCGCCCGCTGGGGCCCGCGATG

DNA

CGCACGGCCGGCTGCGGAGGATCACCTACGTGGTGCACCCGGGCCCCGGCCTGGCAGC
SeqtleriCC

CGGCGCCTTGCCCCTGAGCGGGCCCCCGCGTTCGCGGACATTCAACGTCGCGCTCAAC

GCCAGGTACAGCCGCAGCTCGGCGGCTGCCGGCGCCCCCAGCCGTGCCTCCCCCGGGG

TCCCCTCGGAGAGGACCCGGCGCACGAGCAAGCCGGGCGGCGCGGCCCTGCAGGGGCT

CAGACCGCCGCCGCCGCCGCCGCCGGAGCCTGCGCGTCCCGCGGTCCCCGGCGGGCAG

CTCCACCCCAATCCCGGCGGCCACCCGGCAGCCGCCCCGTTCACCAAACAAGGCAGGC

AAGTTGTGCGCTCCAAGGTGCCGCAGGAGACCCAGAGCGGCGGAGGCTCTAGGCTGCA

GGTTCACCAGAAGCAGCAGCTGCAGGGGGTCAATGTCTGTGGAGGGCGGTGCTGTCAT

GGCTGGAGTAAGGCCCCTGGCTCCCAGAGGTGCACCAAACCTAGCTGTGTTCCGCCAT

GTCAGAATGGAGGGATGTGTCTCCGGCCACAACTCTGTGTGTGTAAACCAGGGACCAA

GGGCAAAGCCTGTGAAACAATAGCTGCCCAGGACACCTCGTCACCAGTCTTTGGAGGG

CAGAGTCCTGGGGCTGCTTCCTCGTGGGGCCCTCCTGAGCAAGCAGCAAAGCATACTT

CATCTAAGAAGGCAGACACTCTACCAAGAGTCAGCCCTGTGGCCCAGATGACCTTAAC

CCTCAAGCCGAAGCCTTCAGTGGGACTCCCCCAGCAGATACATTCTCAAGTGACTCCT

CTTTCTTCCCAGAGCGTGGTTATTCACCATGGCCAGACCCAGGAATACGTGCTCAAGC

CCAAGTACTTTCCAGCCCAGAAGGGGATTTCAGGAGAACAGTCCACTGAAGGTTCTTT

CCCTTTAAGATATGTGCAGGATCAAGTTGCGGCACCTTTTCAGCTGAGTAACCACACT

GGCCGCATCAAGGTGGTCTTTACTCCGAGCATCTGTAAAGTGACCTGCACCAAGGGCA
GCTGTCAGAACAGCTGTGAGAAGGGGAACACCACCACTCTCATTAGTGAGAATGGTCA
TGCTGCCGACACCCTGACGGCCACGAACTTCCGAGTGGTAATTTGCCATCTTCCATGT
ATGAATGGTGGCCAGTGCAGTTCAAGGGACAAATGTCAGTGCCCTCCAAATTTCACAG
GAAAACTTTGTCAGATCCCAGTCCATGGTGCCAGCGTGCCTAAACTTTATCAGCATTC
CCAGCAGCCAGGCAAGGCGTTGGGGACGCATGTCATCCATTCAACACATACCTTGCCT
CTGACCGTGACTAGCCAGCAAGGAGTCAAAGTGAAATTTCCTCCTAACATAGTCAATA
TCCATGTGAAACATCCTCCTGAAGCTTCCGTCCAGATACATCAGGTTTCAAGAATTGA
TGGCCCAACAGGCCAGAAGACAAAAGAAGCTCAACCAGGCCAATCCCAAGTCTCGTAC
CAAGGGCTTCCTGTCCAGAAGACCCAGACCATACATTCCACATACTCCCACCAGCAGG
TCATTCCTCACGTCTACCCCGTGGCTGCTAAGACACAGCTTGGCCGGTGCTTCCAGGA
AACCATTGGGTCACAGTGTGGCAAAGCGCTCCCTGGCCTTTCAAAGCAAGAGGACTGC
TGTGGAACTGTGGGTACCTCCTGGGGCTTTAACAAATGCCAGAAATGCCCCAAGAAAC
CATCTTATCATGGATACAACCAAATGATGGAATGCCTACCGGGTTATAAGCGGGTTAA
CAACACCTTTTGCCAAGATATTAATGAATGTCAGCTACAAGGTGTATGCCCTAATGGT
GAGTGTTTGAATACCATGGGCAGCTATCGATGTACCTGCAAAATAGGATTTGGGCCGG
ATCCTACCTTTTCAAGTTGTGTTCCTGATCCCCCTGTGATCTCGGAAGAGAAAGGGCC
CTGTTACCGACTTGTCAGTTCTGGAAGACAGTGTATGTACCCTCTGTCTGTTCACCTC
ACCAAGCAGCTCTGCTGTTGTAGTGTGGGCAAGGCTGGGCCACACTGTGAGAAATGTC
CCCTTCCAGGCACAGCTGCTTTTAAGGAAATCTGTCCTGGTGGAATGGGTTATACGGT
TTCTGGCGTTCATAGACGCAGGCCAATCCATCACCATGTAGGTAAAGGACCTGTATTT
GTCAAGCCAAAGAACACTCAACCTGTTGCTAAAAGTACTCATCCTCCACCTCTCCCAG
CCAAGGAAGAGCCAGTGGAGGCCCTGACCTTCTCCCGGGAACACGGGGCCAGGAGTGC
GGAGCCAGAAGTGGCAACTGCACCCCCTGAAAAGGAAATACCTTCATTGGATCAAGAG
AAAACCAAACTTGAGCCTGGTCAACCCCAGCTGTCTCCAGGCATTTCCGCTATTCATC
TGCATCCACAGTTTCCAGTAGTGATTGAAAAAACATCACCTCCTGTGCCTGTTGAAGT
AGCTCCTGAAGCTTCTACGTCTAGTGCCAGCCAAGTGATTGCTCCTACTCAAGTGACA
GAAATCAATGAATGTACTGTGAACCCTGATATCTGTGGAGCAGGACACTGCATTAACC
TACCAGTGAGATATACCTGTATATGCTACGAGGGCTACAGGTTCAGTGAACAACAGAG
GAAATGTGTGGATATTGATGAGTGTACTCAGGTCCAACACCTCTGCTCCCAGGGCCGC
TGTGAAAACACCGAGGGAAGTTTCTTGTGCATTTGCCCAGCAGGATTTATGGCCAGTG
AGGAGGGTACTAACTGCATAGATGTTGACGAATGCCTGAGGCCGGACGTCTGTGGGGA
GGGGCACTGTGTCAATACTGTGGGGGCCTTCCGGTGTGAATACTGTGACAGCGGGTAC
CGCATGACTCAGAGAGGCCGTTGTGAGGATATTGATGAATGTTTGAATCCAAGCACTT
GTCCAGATGAGCAGTGTGTGAATTCTCCTGGATCTTACCAGTGCGTTCCCTGCACAGA
AGGATTCCGAGGCTGGAATGGACAGTGCCTTGATGTGGACGAGTGCCTGGAACCAAAC
GTCTGCGCAAATGGTGATTGTTCCAACCTTGAAGGCTCCTACATGTGTTCATGCCACA
AAGGCTATACCCGGACTCCGGACCACAAGCACTGTAGAGATATTGATGAATGTCAGCA
AGGGAATCTATGTGTAAACGGGCAGTGCAAAAATACCGAGGGCTCCTTCAGGTGCACC
TGTGGACAGGGGGGTTACCAGCTGTCGGCAGCTAAAGACCAGTGTGAAGACATTGATG
AATGCCAGCACCGTCATCTCTGTGCTCATGGGCAGTGCAGGAACACTGAGGGCTCTTT
TCAATGTGTGTGTGACCAGGGTTACAGAGCATCTGGGCTTGGAGACCACTGTGAAGAT
TTAATACTG
CAGGGTCCTATGATTGTACTTGTCCGGATGGATTTCAGCTAGATGACAATAAAACATG
TCAAGATATTAATGAATGTGAACATCCAGGGCTCTGTGGTCCACAAGGGGAGTGCCTA
AACACAGAGGGTTCTTTCCATTGTGTCTGCCAGCAGGGTTTCTCAATCTCTGCAGATG
GCCGTACGTGTGAAGATGTGAATGAATGTGAACTGCTCAGTGGGGTGTGTGGTGAAGC
CTTCTGTGAAAACGTGGAAGGGTCCTTCCTGTGCGTGTGTGCTGATGAAAACCAAGAG
TACAGCCCCATGACTGGGCAGTGCCGCTCCCGGACCTCCACAGATTTAGATGTAGATG
TAGATCAACCCAAAGAAGAAAAGAAAGAATGCTACTATAATCTCAATGACGCCAGTCT
CTGTGATAATGTGTTGGCCCCCAATGTCACGAAACAAGAATGCTGCTGTACATCAGGC
GCGGGATGGGGAGATAACTGCGAAATCTTCCCCTGCCCGGTCTTGGGAACTGCTGAGT
TCACTGAAATGTGTCCCAAAGGGAAAGGTTTTGTGCCTGCTGGAGAATCATCTTCTGA
AGCTGGTGGTGAGAACTATAAAGATGCAGATGAATGCCTACTTTTTGGACAAGAAATC
TGCAAAAATGGTTTCTGTTTGAACACTCGGCCTGGGTATGAATGCTACTGTAAGCAAG
GGACGTACTATGATCCTGTGAAACTGCAGTGCTTTGATATGGATGAATGTCAAGACCC
CAGTAGTTGTATTGATGGCCAGTGTGTTAATACAGAGGGCTCTTACAACTGCTTCTGT
ACTCACCCCATGGTCCTGGATGCGTCAGAAAAAAGATGTATACGACCGGCTGAGTCAA
ACGAACAAATAGAAGAAACTGATGTCTACCAAGATTTGTGCTGGGAACATCTGAGTGA
TGAATACGTGTGTAGCCGGCCTCTTGTGGGCAAGCAGACAACGTACACTGAGTGCTGC
TGTCTGTATGGAGAGGCCTGGGGCATGCAGTGTGCCCTCTGCCCCCTGAAGGATTCAG

ATGACTATGCTCAGCTGTGTAACATCCCCGTGACGGGACGCCGGCAGCCATATGGACG
GGACGCCTTGGTTGACTTCAGTGAACAGTATACTCCAGAAGCCGATCCCTACTTCATC
CAAGACCGTTTTCTAAATAGCTTTGAGGAGTTACAGGCTGAGGAATGCGGCATCCTCA
ATGGATGTGAAAATGGTCGCTGTGTGAGGGTCCAGGAAGGTTACACCTGCGATTGCTT
TGATGGGTATCACTTGGATACGGCCAAGATGACCTGTGTCGATGTAAATGAATGCGAT
GAGTTGAACAACCGGATGTCTCTCTGCAAGAATGCCAAGTGCATTAACACCGATGGTT
CCTACAAGTGTTTGTGTCTGCCAGGCTACGTGCCTTCTGACAAGCCAAACTACTGCAC
TCCGTTGAATACCGCCTTGAATTTAGAGAAAGACAGTGACCTGGAGTGAAACAGAATC
TACATAACCTAAGCCCATATACTCTGCACTGTGTAAAGGAAAAGGGAGAAATGTATTA
TACTTGAGACATTGCACCTACCCCGGAAGGCTGGAAATACGGAAACAGCATGGAGTTG
CAAGTCCTCTGAAGACAATGAGAGGATTTAGGATGAGCCCGATAGGTGTGGCAGACCA
AATGGACATTTCTCTAAAAAACCAGTATATATAGTCTGTTCATATGTAAAATTCAATG
GAAGAGAGGTGGAACAGTGCTGTTATTTTAAACAGAAGGTTGTATTATTATGTTGTTT
TGTTTTTTTACTATTGCTTGATTAAATTTGGCATTTAAATAGTGGTGGAAATATTTTA
TATAATTTTCATTTTTTGGTTGTGCAGTTCCTTGGCTACTGTTTTTCTTTTACTTCAG
TTTTTTAAAAATCTCAAATGAAAAAGTCTTCGATACAATATTGTTAAGCTGTATTATA
AGTATTGTTACACAGGGTTATGCAATTCCCGGCCTGGAGCATTTTTGAAATTCAAATT
GTCTGTCCTGTGGAGCAGGCAGTGATTTTGTTCCAAAACTTTGTATACACATTTGGAG
AAAAGTACTTTATATTTTCAGTGTTTTGTCTGATTTTAATGTCCGTTCTTAGCCAAGC
TGCTAGCAGGTGTTAATTGGATCCCTTTCCTTCACTGAAATGGAAGAGTTTATAAGCT
TACGTTAGTATTGTAATATGTAAAGTAAGCCCAACAAAAATTTTTAAAAATTTGATGA
TCCCCAATATATCTACCATTGTATGTTAAATAAATCACCATTTTTGTAGAAAAAATTC
TACCTGAGAGTAATTGTCAATGAGTACATGTGTATAAGTTGTATCCCACTCTCCCCAC
TTTTATCTTTTCCAGTGGTCTTCTGTTAATGTAGTGTCTTTTACAAGTTAATCATTAA
ORF Start: ATG at 56 ORF Stop: TGA at 5093 SEQ ID NO: 170 1679 as MW at 182193.4kD
NOV37C, MAGAWLRWGLLLWAGLLASSAHGRLRRITYVVHPGPGLAAGALPLSGPPRSRTFNVAL
CGS9819-O3 PrOtelri N~YSRSSAAAGAPSRASPGVPSERTRRTSKPGGAALQGLRPPPPPPPEPARPAVPGG
Se uence QLHPNPGGHPAAAPFTKQGRQWRSKVPQETQSGGGSRLQVHQKQQLQGVNVCGGRCC
q HGWSKAPGSQRCTKPSCVPPCQNGGMCLRPQLCVCKPGTKGKACETIAAQDTSSPVFG
GQSPGAASSWGPPEQAAKHTSSKKADTLPRVSPVAQMTLTLKPKPSVGLPQQIHSQVT
PLSSQSWIHHGQTQEYVLKPKYFPAQKGISGEQSTEGSFPLRYVQDQVAAPFQLSNH
TGRIKWFTPSICKVTCTKGSCQNSCEKGNTTTLISENGHAADTLTATNFRWICHLP
CMNGGQCSSRDKCQCPPNFTGKLCQIPVHGASVPKLYQHSQQPGKAI~GTHVIHSTHTL
PLTVTSQQGVKVKFPPNIVNIHVKHPPEASVQIHQVSRIDGPTGQKTKEAQPGQSQVS
YQGLPVQKTQTIHSTYSHQQVIPHVYPVAAKTQLGRCFQETIGSQCGKALPGLSKQED
CCGTVGTSWGFNKCQKCPKKPSYHGYNQMMECLPGYKRVNNTFCQDINECQLQGVCPN
GECLNTMGSYRCTCKIGFGPDPTFSSCVPDPPVISEEKGPCYRLVSSGRQCMYPLSVH
LTKQLCCCSVGKAGPHCEKCPLPGTAAFKEICPGGMGYTVSGVHRRRPIHHHVGKGPV
FVKPKNTQPVAKSTHPPPLPAKEEPVEALTFSREHGARSAEPEVATAPPEKEIPSLDQ
EKTKLEPGQPQLSPGISAIHLHPQFPWIEKTSPPVPVEVAPEASTSSASQVIAPTQV
TEINECTVNPDICGAGHCINLPVRYTCICYEGYRFSEQQRKCVDIDECTQVQHLCSQG
RCENTEGSFLCICPAGFMASEEGTNCIDVDECLRPDVCGEGHCVNTVGAFRCEYCDSG
YRMTQRGRCEDIDECLNPSTCPDEQCVNSPGSYQCVPCTEGFRGWNGQCLDVDECLEP
', NVCANGDCSNLEGSYMCSCHKGYTRTPDHKHCRDIDECQQGNLCVNGQCKNTEGSFRC
TCGQGGYQLSAAKDQCEDIDECQHRHLCAHGQCRNTEGSFQCVCDQGYRASGLGDHCE
DINECLEDKSVCQRGDCINTAGSYDCTCPDGFQLDDNKTCQDINECEHPGLCGPQGEC
LNTEGSFHCVCQQGFSISADGRTCEDVNECELLSGVCGEAFCENVEGSFLCVCADENQ
EYSPMTGQCRSRTSTDLDVDVDQPKEEKKECYYNLNDASLCDNVLAPNVTKQECCCTS
GAGWGDNCEIFPCPVLGTAEFTEMCPKGKGFVPAGESSSEAGGENYKDADECLLFGQE
ICKNGFCLNTRPGYECYCKQGTYYDPVKLQCFDMDECQDPSSCIDGQCVNTEGSYNCF
CTHPMVLDASEKRCIRPAESNEQIEETDVYQDLCWEHLSDEYVCSRPLVGKQTTYTEC
CCLYGEAWGMQCALCPLKDSDDYAQLCNIPVTGRRQPYGRDALVDFSEQYTPEADPYF
IQDRFLNSFEELQAEECGILNGCENGRCVRVQEGYTCDCFDGYHLDTAKMTCVDVNEC
DELNNRMSLCKNAKCINTDGSYKCLCLPGYVPSDKPNYCTPLNTALNLEKDSDLE
Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 37B.

Table 37B. Comparison of NOV37a against NOV37b through NOV37c.
Protein Sequence NOV37a Residues/ Identities/
Match Residues Similarities for the Matched Region NOV37b 19..1721 1561/1703 (91%) 19..1668 1562/1703 (91%) NOV37c 19..1721 1565/1704 (91%) 19..1679 ~ 1565/1704 (91%) Further analysis of the NOV37a protein yielded the following properties shown in Table 37C.
Table 37C. Protein Sequence Properties NOV37a PSort 0.3700 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1000 probability located in endoplasmic reticulum (membrane);
0.1000 probability located in endoplasmic reticulum (lumen) SignalP Likely cleavage site between residues 24 and 25 analysis:
A search of the NOV37a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publications, yielded several homologous proteins shown in Table 37D.
Table 37D. Geneseq Results for NOV37a NOV37a Identities/

Geneseq Protein/Organism/Length Residues/Similarities Expect [Patent for Identifier#, Date] Match the Matched Value ResiduesRegion AAR22461Masking protein high polymer1..1721 1525/1721 0.0 unit (88%) precursor MPU-P - Rattus 1..1712 1603/1721 rattus, (92%) 1712 aa. [JP04066597-A, 1992]

AAR14584TGF beta 1 binding protein342..17211324/1380 0.0 encoded (95%) by clone BPA 13 - Homo 16..13551326/1380 sapiens, (95%) 1355 aa. [W09113152-A, OS-SEP-1991]

AAR53089Human masking protein 742..1586841/845 (99%)0.0 subunit hMPU-P - Homo sapiens, 1..845 841/845 (99%) 845 aa.

[JP06092995-A, OS-APR-1994]

AAR53086Human masking protein 832..1586752/755 (99%)0.0 subunit hMPU-1 - Homo Sapiens, 2..756 752/755 (99%) 756 aa.

[JP06092995-A, OS-APR-1994]

AAR53087 0.0 hMPU-2 - Homo Sapiens, 752 aa. 1..752 749/752 (99%) [JP06092995-A, OS-APR-1994]
In a BLAST search of public sequence databases, the NOV37a protein was found to have homology to the proteins shown in the BLASTP data in Table 37E.
Table 37E. Public BLASTP
Results for NOV37a ..."""""""."",.,.,....."""..."".. NOV37a Identities/

Protein Residues/SimilaritiesExpect for AccessionProtein/Organism/Length Match the Matched Value Number ResiduesPortion Q00918 Latent transforming growth 1..1721 1536/1721 0.0 factor beta (89%) binding protein 1 precursor1..1712 1611/1721 (93%) (Transforming growth factor beta-1 binding protein 1 ) (TGF-beta 1-BP- 1 ) (Transforming growth factor beta-1 masking protein, large subunit) - Rattus norvegicus (Rat), 1712 aa.

088349 LATENT TGF BETA BINDING 1..1720 1523/1721 0.0 (88%) PROTEIN - Mus musculus (Mouse),1..1712 1603/1721 (92%) 1713 aa.

P22064 Latent transforming growth 342..17211369/1380 0.0 factor beta (99%) binding protein 1 precursor16..13941370/1380 (99%) (Transforming growth factor beta-1 binding protein 1) (TGF-betal-BP-1) -Homo sapiens (Human), 1394 aa.

035806 LATENT TGF-BETA BINDING 72..1705710/1748 0.0 (40%) PROTEIN-2 LIKE PROTEIN - 75..1760937/1748 Rattus (52%) norvegicus (Rat), 1764 aa.

Q14767 LATENT TRANSFORMING 74..1706693/1810 0.0 (38%) GROWTH FACTOR-BETA- 87..1818919/1810 (50%) BINDING PROTEIN-2 (LTBP-2) -Homo Sapiens (Human), 1821 aa.

PFam analysis predicts that the NOV37a protein contains the domains shown in the Table 37F.
Table 37F. Domain Analysis of NOV37a --Identities/
Pfam Domain NOV37a Match Similarities Expect Region for the Matched Value Region EGF: domain 1 of 18 191..218 15/47 (32%) 0.0056 19/47 (40%) EGF: domain 2 of 18 403..430 15/47 (32%) 0.00014 23/47 (49%) wap: domain 1 of 1 385..433 12/57 (21%) 9.3 30/57 (53%) TB: domain 1 of 4 566..609 15/48 (31 %) 6e-13 41/48 (85%) EGF: domain 3 of 18 630..665 14/47 (30%) le-OS

27/47 (57%) Keratin_B2: domain 578..717 40/180 (22%) 1.5 1 of 1 64/180 (36%) TB: domain 2 of 4 687..728 25/47 (53%) 1.1e-21 40/47 (85%) Arthro_defensin: domain874..901 9/37 (24%) 8.4 1 of 1 18/37 (49%) EGF: domain 4 of 18 877..913 15/47 (32%) 1.8e-05 27/47 (57%) EGF: domain 5 of 18 919..955 15/47 (32%) 6e-OS

27/47 (57%) granulin: domain 1 942..957 6/16 (38%) 0.57 of 2 12/16 (75%) EGF: domain 6 of 18 961..996 15/47 (32%) 7.9 22/47 (47%) EGF: domain 7 of 18 1002..1036 13/47 (28%) 50 27/47 (57%) EGF: domain 8 of 18 1042..1077 15/47 (32%) 0.00066 24/47 (51 %) EGF: domain 9 of 18 1083..1118 16/47 (34%) 0.00019 30/47 (64%) EGF: domain 10 of 1124..1159 14/47 (30%) 0.00026 28/47 (60%) EGF: domain 11 of 1165..1200 14/47 (30%) 0.0071 26/47 ($5%) EGF: domain 12 of 1206..1242 13/47 (28%) 0.00073 27/47 (57%) granulin: domain 2 1226..1244 10/19 (53%) 20 of 2 15/19 (79%) EGF: domain 13 of 1248..1284 13/47 (28%) 0.00063 25/47 (53%) EGF: domain 1,4 of 1290..1327 0.0037 18 ~.~

27/47 (S7%) TB: domain 3 of 1357..1400 24/47 (S1%) 2e-18 36/47 (77%) EGF: domain 1 S 1428..1465 14/47 (30%) 0.014 of 18 27/47 (S7%) EGF: domain 16 of 1471..1 S06 1 S/47 (32%) 1.2e-OS

29/47 (62%) TB: domain 4 of 1534..1576 18/47 (38%) 8.6e-18 40/47 (8S%) EGF: domain 17 of 1625..1660 16/47 (34%) 0.0004 26/47 (SS%) EGF: domain 18 of 1666..1705 16/49 (33%) S.Be-06 31/49 (63%) EXAMPLE 38.

The NOV38 clone was analyzed, and the nucleotide and predicted polypeptide sequences are shown in Table 38A.
Table 38A. NOV38 Sequence Analysis SEQ ID NO: 171 ] 1034 by NOV3Ha, ~GCGGCCGCCCCGGCGGCTCCTGGAACCCCGGTTCGCGGCGATGCCAGCCACCCCAGCG
CGS968S-O1 ~GCCGCCGCAGTTCAGTGCTTGGATAATTTGAAAGTACAATAGTTGGTTTCCCTGTC
DNA

CACCCGCCCCACTTCGCTTGCCATCACAGCACGCCTATCGGATGTGAGAGGAGAAGTC

Sequence CCGCTGCTCGGGCACTGTCTATATACGCCTAACACCTACATATATTTTAAAAACATTA

AATATAATTAACAATCAAAAGAAAGAGGAGAAAGGAAGGGAAGCATTACTGGGTTACT

ATGCACTTGCGACTGATTTCTTGGCTTTTTATCATTTTGAACTTTATGGAATACATCG

GCAGCCAAAACGCCTCCCGGGGAAGGCGCCAGCGAAGAATGCATCCTAACGTTAGTCA

AGGCTGCCAAGGAGGCTGTGCAACATGCTCAGATTACAATGGATGTTTGTCATGTAAG

CCCAGACTATTTTTTGCTCTGGAAAGAATTGGCATGAAGCAGATTGGAGTATGTCTCT

CTTCATGTCCAAGTGGATATTATGGAACTCGATATCCAGATATAAATAAGTGTACAAG

TAAGTGCCCACACGAAAAAGCTGACTGTGATACCTGTTTCAACAAAAATTTCTGCACA

AAATGTAAAAGTGGATTTTACTTACACCTTGGAAAGTGCCTTGACAATTGCCCAGAAG

GGTTGGAAGCCAACAACCATACTATGGAGTGTGTCAGTTCAGTGCACTGTGAGGTCAG

TGAATGGAATCCTTGGAGTCCATGCACGAAGAAGGGAAAAACATGTGGCTTCAAAAGA

GGGACTGAAACACGGGTCCGAGAAATAATACAGCATCCTTCAGCAAAGGGTAACCTGT

GTCCCCCAACAAATGAGACAAGAAAGTGTACAGTGCAAAGGAAGAAGTGTCAGAAGGG

AGAACGAGGTACAATCATAATAACAAAATGTGCTTGTTTGAATCCTCATAATCTGTTG

CATTTTTCATTTTATTTCTTATGAAACACTTGGCATTATCTTTCATGC

ORF Start: ATG at ORF
291 Stop:
TGA
at SEQ ID NO: 172 239 MW at 27062.11cD
as NOV38a, MHLRLISWLFIILNFMEYIGSQNASRGRRQRRMHPNVSQGCQGGCATCSDYNGCLSCK

CGS96HS-Ol PRLFFALERIGMKQIGVCLSSCPSGYYGTRYPDINKCTSKCPHEKADCDTCFNKNFCT

PCOtelri KCKSGFYLHLGKCLDNCPEGLEANNHTMECVSSVHCEVSEWNPWSPCTKKGKTCGFKR

SequeriCe GTETRVREIIQHPSAKGNLCPPTNETRKCTVQRKKCQKGERGTIIITKCACLNPHNLL

HFSFYFL

SEQ ID NO: 173 ~ S8S by NOV3Hb, GGATCCCAAAACGCCTCCCGGGGAAGGCGCCAGCGAAGAATGCATCCTAACGTTAGTC
AAGGCTGCCGAGGAGGCTGTGCAACATGCTCAGATTACAATGGATGTTTGTCATGTAA

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

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Claims

We claim:

1. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of:
a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86;
b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed;
c) the amino acid sequence selected from the group consisting of SEQ ID NO:
2n, wherein n is an integer between 1 and 86;
d) a variant of the amino acid sequence selected from the group consisting of SEQ ID
NO: 2n, wherein n is an integer between 1 and 86, wherein any amino acid , specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed;
and e) a fragment of any of a) through d).

2. The polypeptide of claim 1 that is a naturally occurring allelic variant of the sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86.

3. The polypeptide of claim 2, wherein the allelic variant comprises an amino acid sequence that is the translation of a nucleic acid sequence differing by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 2n, wherein n is an integer between 1 and 86.

4. The polypeptide of claim 1 that is a variant polypeptide described therein, wherein any amino acid specified in the chosen sequence is changed to provide a conservative substitution.

5. A pharmaceutical composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier.

6. A kit comprising in one or more containers, the pharmaceutical composition of claim 5.

7. The use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease selected from a pathology associated with the polypeptide of claim 1, wherein the therapeutic is the polypeptide of claim 1.

8. A method for determining the presence or amount of the polypeptide of claim 1 in a sample, the method comprising:
(a) providing the sample;
(b) introducing the sample to an antibody that binds immunospecifically to the polypeptide; and (c) determining the presence or amount of antibody bound to the polypeptide, thereby determining the presence or amount of polypeptide in the sample.

9. A method for determining the presence of or predisposition to a disease associated with altered levels of the polypeptide of claim 1 in a first mammalian subject, the method comprising:
a) measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and b) comparing the amount of the polypeptide in the sample of step (a) to the amount of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, the disease, wherein an alteration in the expression level of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

10. A method of identifying an agent that binds to the polypeptide of claim 1, the method comprising:
(a) introducing the polypeptide to the agent; and (b) determining whether the agent binds to the polypeptide.

11. The method of claim 10 wherein the agent is a cellular receptor or a downstream effector.

12. A method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of the polypeptide of claim 1, the method comprising:

(a) providing a cell expressing the polypeptide of claim 1 and having a property or function ascribable to the polypeptide;

(b) contacting the cell with a composition comprising a candidate substance;
and (c) determining whether the substance alters the property or function ascribable to the polypeptide;
whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition devoid of the substance, the substance is identified as a potential therapeutic agent.

13. A method for screening for a modulator of activity or of latency or predisposition to a pathology associated with the polypeptide of claim 1, the method comprising:
a) administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of claim 1, wherein the test animal recombinantly expresses the polypeptide of claim 1;
b) measuring the activity of the polypeptide in the test animal after administering the compound of step (a); and c) comparing the activity of the protein in the test animal with the activity of the polypeptide in a control animal not administered the polypeptide, wherein a change in the activity of the polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency of, or predisposition to, a pathology associated with the polypeptide of claim 1.

14. The method of claim 13, wherein the test animal is a recombinant test animal that expresses a test protein transgene or expresses the transgene under the control of a promoter at an increased level relative to a wild-type test animal, and wherein the promoter is not the native gene promoter of the transgene.

15. A method for modulating the activity of the polypeptide of claim 1, the method comprising introducing a cell sample expressing the polypeptide of the claim with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide.

16. A method of treating or preventing a pathology associated with the polypeptide of claim 1, the method comprising administering the polypeptide of claim 1 to a subject in which such treatment or prevention is desired in an amount sufficient to treat or prevent the pathology in the subject.

17. The method of claim 16, wherein the subject is a human.

18. A method of treating a pathological state in a mammal, the method comprising administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 86, or a biologically active fragment thereof.

19. An isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of:
a) a mature form of the amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 86;
b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed;

c) the amino acid sequence selected from the group consisting of SEQ ID NO:
2n, wherein n is an integer between 1 and 86;
d) a variant of the amino acid sequence selected from the group consisting of SEQ ID
NO: 2n, wherein n is an integer between 1 and 86, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed;
e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 86, or any variant of the polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and f) the complement of any of the nucleic acid molecules.

20. The nucleic acid molecule of claim 19, wherein the nucleic acid molecule comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant.

21. The nucleic acid molecule of claim 19 that encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant.

22. The nucleic acid molecule of claim 19, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID
NOS: 2n-1, wherein n is an integer between 1 and 86.

23. The nucleic acid molecule of claim 19, wherein the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of a) the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 86;
b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 86, is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed;
c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ
ID NO: 2n-1, wherein n is an integer between 1 and 86; and d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 86, is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed.

24. The nucleic acid molecule of claim 19, wherein the nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ
ID NO: 2n-1, wherein n is an integer between 1 and 86, or a complement of the nucleotide sequence.

25. The nucleic acid molecule of claim 19, wherein the nucleic acid molecule comprises a nucleotide sequence in which any nucleotide specified in the coding sequence of the chosen nucleotide sequence is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides in the chosen coding sequence are so changed, an isolated second polynucleotide that is a complement of the first polynucleotide, or a fragment of any of them.

26. A vector comprising the nucleic acid molecule of claim 19.

27. The vector of claim 26, further comprising a promoter operably linked to the nucleic acid molecule.

28. A cell comprising the vector of claim 27.

29. A method for determining the presence or amount of the nucleic acid molecule of claim 19 in a sample, the method comprising:
(a) providing the sample;

(b) introducing the sample to a probe that binds to the nucleic acid molecule;
and (c) determining the presence or amount of the probe bound to the nucleic acid molecule, thereby determining the presence or amount of the nucleic acid molecule in the sample.

30. The method of claim 29 wherein presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type.

31. The method of claim 30 wherein the cell or tissue type is cancerous.

32. A method for determining the presence of or predisposition to a disease associated with altered levels of the nucleic acid molecule of claim 19 in a first mammalian subject, the method comprising:
a) measuring the amount of the nucleic acid in a sample from the first mammalian subject; and b) comparing the amount of the nucleic acid in the sample of step (a) to the amount of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease;
wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.